U.S. patent application number 16/036678 was filed with the patent office on 2018-11-22 for methods of treatment.
The applicant listed for this patent is Bow River LLC. Invention is credited to Christina CHOW, Sundar SRINIVASAN.
Application Number | 20180333411 16/036678 |
Document ID | / |
Family ID | 64269934 |
Filed Date | 2018-11-22 |
United States Patent
Application |
20180333411 |
Kind Code |
A1 |
SRINIVASAN; Sundar ; et
al. |
November 22, 2018 |
METHODS OF TREATMENT
Abstract
The present disclosure provides for methods of treating a
patient with a CYP3A4 substrate drug contraindicated for
concomitant administration with a strong CYP3A4 inhibitor, wherein
the patient is treated with multiple doses of posaconazole, stops
posaconazole treatment, and then is treated with the CYP3A4
substrate drug. In some embodiments, treatment with the CYP3A4
substrate drug is delayed for about 5-21 after stopping
posaconazole. In some embodiments, the patient is treated with or
prescribed a reduced dose of the CYP3A4 substrate drug for about
5-21 after stopping posaconazole.
Inventors: |
SRINIVASAN; Sundar; (Corona
Del Mar, CA) ; CHOW; Christina; (Newport Beach,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bow River LLC |
Corona Del Mar |
CA |
US |
|
|
Family ID: |
64269934 |
Appl. No.: |
16/036678 |
Filed: |
July 16, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15596585 |
May 16, 2017 |
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16036678 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/496 20130101;
A61K 31/4985 20130101; A61K 31/495 20130101 |
International
Class: |
A61K 31/496 20060101
A61K031/496 |
Claims
1. A method of treating a patient with a CYP3A4 substrate drug
contraindicated for concomitant administration with a strong CYP3A4
inhibitor, comprising: (a) treating a patient with multiple doses
of posaconazole; (b) stopping posaconazole treatment; (c) delaying
administration of the CYP3A4 substrate drug after step (b) for up
to about 7 days; then (d) administering a dose of the CYP3A4
substrate drug which is not more than about 50% of the reference
dose of the CYP3A4 substrate drug during a time period of 5-21 days
after stopping posaconazole treatment.
2. The method of claim 1, wherein the patient is treated with or
prescribed the CYP3A4 substrate drug for a disease or condition
selected from the group consisting of hormone receptor
(HR)-positive, human epidermal growth factor receptor 2
(HER2)-negative advanced or metastatic breast cancer with disease
progression following endocrine therapy in women in combination
with fulvestrant, as monotherapy for the treatment of adult
patients with HR-positive, HER2-negative advanced or metastatic
breast cancer with disease progression following endocrine therapy
and prior chemotherapy in the metastatic setting, cystic fibrosis
(CF) in patients age 2 years and older who have one mutation in the
CFTR gene that is responsive to ivacaftor based on clinical and/or
in vitro assay data, deleterious or suspected deleterious germline
BRCA-mutated advanced ovarian cancer in adult patients who have
been treated with three or more prior lines of chemotherapy,
intermediate or high-risk myelofibrosis, including primary
myelofibrosis, post-polycythemia vera myelofibrosis and
post-essential thrombocythemia myelofibrosis, polycythemia vera
patients who have had an inadequate response to or are intolerant
of hydroxyurea, as an adjunctive therapy to antidepressants for the
treatment of major depressive disorder (MDD), schizophrenia, cystic
fibrosis (CF) patients aged 12 years and older who are homozygous
for the F508del mutation or who have at least one mutation in the
cystic fibrosis transmembrane conductance regulator (CFTR) gene
that is responsive to tezacaftor/ivacaftor based on in vitro data
and/or clinical evidence, metastatic colorectal cancer (CRC)
patients who have been previously treated with fluoropyrimidine-,
oxaliplatin- and irinotecan-based chemotherapy, an antiVEGF
therapy, and, if RAS wild-type, an anti-EGFR therapy, locally
advanced, unresectable or metastatic gastrointestinal stromal tumor
(GIST) patients who have been previously treated with imatinib
mesylate and sunitinib malate, hepatocellular carcinoma (HCC) who
have been previously treated with sorafenib, chronic HCV genotype 1
or 3 infection with sofosbuvir and with or without ribavirin,
metastatic non-small cell lung cancer (NSCLC) in patients whose
tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as
detected by an FDA-approved test, opioid induced constipation (OIC)
in adult patients with chronic non-cancer pain, including patients
with chronic pain related to prior cancer or its treatment who do
not require frequent (e.g., weekly) opioid dosage escalation,
unresectable or metastatic melanoma in patients with BRAF V600E
mutation as detected by an FDA-approved test, in combination with
trametinib, for unresectable or metastatic melanoma in patients
with BRAF V600E or V600K mutations as detected by an FDA-approved
test melanoma in patients with BRAF V600E or V600K mutations, as
detected by an FDA-approved test, and involvement of lymph node(s),
following complete resection, metastatic non-small cell lung cancer
(NSCLC) in patients with BRAF V600E mutation as detected by an
FDA-approved test, locally advanced or metastatic anaplastic
thyroid cancer (ATC) in patients with BRAF V600E mutation and with
no satisfactory locoregional treatment options, and with or without
ribavirin for treatment of chronic HCV genotypes 1 or 4 infection
in adults.
3. The method of claim 1, wherein said CYP3A4 substrate drug is
selected from the group consisting of lurasidone, ranolazine,
lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib
succinate, deflazacort, cinacalcet hydrochloride, pimavanserin
tartrate, aripiprazole lauroxil, cariprazine hydrochloride,
simeprevir sodium, everolimus, saxagliptin hydrochloride,
saxagliptin/metformin hydrochloride, ticagrelor, vilazodone
hydrochloride, apixaban, tofacitinib citrate, eletriptan
hydrobromide, nilotinib hydrochloride monohydrate, dronedarone
hydrochloride, fluticasone propionate/salmeterol xinafoate,
rivaroxaban, tadalafil, ibrutinib, cobimetinib, colchicine,
cabazitaxel, tolvaptan, fosaprepitant dimeglumine, aprepitant,
solifenacin succinate, erlotinib hydrochloride, ado-trastuzumab
ematansine, bosutinib monohydrate, sunitinib malate, fesoterodine
fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,
axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate,
ponatinib hydrochloride, isavuconazonium sulfate, lomitapide
mesylate, iloperidone, palbociclib, levomilnacipran hydrochloride,
pimozide, pomalidomide, abemaciclib, ivacaftor, ruxolitinib
phosphate, brexpiprazole, ivacaftor/tezacaftor, regorafenib,
daclatasvir, crizotinib, naloxegol oxalate, dabrafenib, olaparib,
and elbasvir and grazoprevir.
4. The method of claim 1, wherein said administration of the CYP3A4
substrate drug in step (d) is for about 5-14 days.
5. The method of claim 1, wherein said administration of the CYP3A4
substrate in step (d) is for about 5-10 days.
6. The method of claim 1, wherein said delaying in step (c) is up
to one day.
7. The method of claim 1, wherein the patient is not obese and is a
normal CYP3A4 metabolizer.
8. The method of claim 1, wherein the patient is a poor or
intermediate CYP3A4 metabolizer.
9. The method of claim 1, wherein the patient has a characteristic
selected from at least one of the following: i) BMI of at least
about 35; ii) % IBW of at least about 150%; iii) waist size greater
than about 42 inches; iv) % body fat greater than about 40%; v)
total body fat greater than about 40 kg; and vi) medically
diagnosed as obese.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 15/596,585, filed May 16, 2017, the entire
contents of which are incorporated by reference in its
entirety.
BACKGROUND
[0002] Posaconazole, also called Noxafil and Posanol, is indicated
for the prophylaxis of invasive Aspergillus and Candida infections
in patients who are at high risk of developing these infections due
to being severely immunocompromised, such as hematopoietic stem
cell transplant (HSCT) recipients with graft-versus-host disease
(GVHD) or those with hematologic malignancies with prolonged
neutropenia from chemotherapy, for the treatment of oropharyngeal
candidiasis (OPC), including OPC refractory (rOPC) to itraconazole
and/or fluconazole, the treatment of invasive aspergillosis, and
the treatment of zygomycosis. Posaconazole has also been used
"off-label" for treating allergic bronchopulmonary aspergillosis;
prophylaxis or treatment of recurrent candidiasis for the
esophagus, secondary to HIV infection; Fusarium infections mycosis;
and chronic or cavitary necrotizing pulmonary aspergillosis.
[0003] Posaconazole is a strong inhibitor of the CYP3A4 enzyme, a
member of the cytochrome P450 family of oxidizing enzymes found in
the liver. These Cytochrome P450 enzymes, such as CYP3A4, oxidize
small organic molecules in the body, such as toxins or certain
drugs, thereby deactivating and/or degrading them. Organic
molecules in the body (such as a drug) which are primarily oxidized
by a particular enzyme can be referred to as "substrates" for the
relevant enzyme. A drug which is primarily oxidized by the CYP3A4
enzyme can be referred to as a "CYP3A4 substrate drug."
[0004] The Noxafil label specifically contraindicates the
co-administration of CYP3A4 substrate drug with specific drugs
metabolized by CYP3A4 such as sirolimus, CYP3A4 substrates such as
pimozide and quinidine, HMG-CoA Reductase Inhibitors primarily
metabolized through CYP3A4, and ergot alkaloids, and indicates that
dosage adjustments should be considered when concomitantly
administering posaconazole with other drugs metabolized by CYP3A4,
including Tacrolimus, cyclosporine, vinca alkaloids such as
vincristine and vinblastine, and calcium channel blockers such as
verapamil, diltiazem, nifedipine, nicardipine, and felodipine.
However, while the Noxafil label does identify specific drug-drug
interactions related to concomitant administration of posaconazole
and CYP3A4 substrate drugs, it does not indicate any concerns
regarding the administration of CYP3A4 substrate drugs after
ceasing the administration of posaconazole.
[0005] The present inventors have surprisingly discovered that a
delay in administration of a CYP3A4 substrate drug, or in some
instances a dose adjustment of a CYP3A4 substrate drug for a
specified time interval is required after ceasing the
administration of posaconazole in order to prevent or reduce the
incidence of dangerous side effects of the CYP3A4 substrate
drug.
SUMMARY OF THE INVENTION
[0006] The present disclosure provides for methods of treating a
patient with a CYP3A4 substrate drug contraindicated for
concomitant administration with a strong CYP3A4 inhibitor, wherein
the patient was previously administered a therapeutically effective
regimen of posaconazole.
[0007] Applicants have discovered that although CYP3A4 substrate
drugs are generally only contraindicated for coadministration with
strong CYP3A4 inhibitors, such as posaconazole, CYP3A4 substrate
drugs cannot always be safely administrated immediately after a
patient has stopped posaconazole treatment. Applicants have
discovered that posaconazole accumulation in the body of patients,
particularly for specific patient populations as described herein,
can result in serious and potentially life-threatening side effects
if a CYP3A4 substrate drug is administered too soon, subsequent to
the cessation of a posaconazole regimen. Accordingly, for CYP3A4
substrate drugs, particularly those contraindicated for
coadministration with a strong CYP3A4 inhibitor (including but not
limited to posaconazole), a washout or delay period of about 2-42
days (e.g., 2-21 days) between ceasing administration of the
posaconazole regimen and starting administration of the CYP3A4
substrate drug is required in order to avoid or reduce the
incidence of side effects resulting from administration of the
CYP3A4 substrate drug. Alternatively, rather than delaying
administering the CYP3A4 substrate drug after ceasing
administration of the posaconazole regimen, in some embodiments,
the Applicants have discovered that patients can safely be
administered a reduced dose of the CYP3A4 substrate drug (reduced
relative to the recommended dose of the CYP3A4 substrate drug) for
a period of time (about 2-42 days (e.g., 2-21 days)) following
cessation of the posaconazole regimen, after which the dose of the
CYP3A4 substrate drug can be safely increased to the recommended
level.
[0008] In certain embodiments, the disclosed methods of delaying
treatment with a CYP3A4 substrate drug, or reducing the dose of a
CYP3A4 substrate drug, for about 2-42 days (e.g., 2-21 days) after
ceasing administration of a posaconazole regimen are directed to a
normal patient, e.g., non-obese patients and normal CYP3A4
metabolizers. In certain embodiments, the disclosed methods of
delaying treatment of a CYP3A4 substrate drug, or reducing the dose
of a CYP3A4 substrate drug, for about 2-42 days (e.g., 2-21 days)
after ceasing administration of a posaconazole regimen are directed
to patients having specific physiological characteristics as
described herein. Such patients can exhibit a substantially greater
exposure to the CYP3A4 substrate drug after ceasing administration
of a posaconazole regimen than was previously known, and therefore
after ceasing administration of posaconazole, require substantially
longer "washout" periods prior to starting treatment of a CYP3A4
substrate drug, or require treatment of a reduced dose of the
CYP3A4 substrate drug for a substantially longer period in order to
avoid or reduce the incidence of side effects associated with
treatment of the CYP3A4 substrate drug. More specifically, the
present applicants have found that patients having specific
physiological characteristics as described herein exhibit higher
than expected exposure to a CYP3A4 substrate drug dosed after
ceasing administration of a posaconazole regimen, compared to
"normal" patients (e.g., a patient who is otherwise the same except
for having specific physiological characteristics as described
herein). For example, patients with e.g., BMI values in the
"normal" range (about 18.5-24.9) can exhibit substantially reduced
CYP3A4 substrate drug elimination; such patients may be described
as poor or intermediate CYP3A4 metabolizers. Thus, as disclosed
herein, the present inventors have found that specific patient
populations may require substantially different and longer washout
periods after ceasing administration of posaconazole and prior to
starting treatment with a CYP3A4 substrate drug, or alternatively
treating with a reduced dose of a CYP3A4 substrate drug for a
particular period of time after stopping posaconazole
treatment.
[0009] In various embodiments, the present disclosure provides for
methods of treating a patient by delaying a first use of a CYP3A4
substrate drug until about 2-42 days (e.g., 2-21 days) after
stopping administration of posaconazole. In embodiments, the CYP3A4
substrate drug is a drug contraindicated for concomitant use with a
strong CYP3A4 inhibitor, such as but not limited to posaconazole.
Accordingly, in various embodiments, the present disclosure
provides for methods of treating a patient who has previously been
treated with multiple doses of posaconazole, with a CYP3A4
substrate drug contraindicated for concomitant treatment with a
strong CYP3A4 inhibitor, said method comprising first treating the
patient, or prescribing the first treatment to begin, with a dose
of the CYP3A4 substrate drug at least 2-42 days (e.g., 2-21 days)
after stopping a posaconazole treatment.
[0010] In various embodiments, the present disclosure provides for
methods of treating a patient, or prescribing the first treatment
to begin, with a CYP3A4 substrate drug at a dose which is less than
or equal to about 50% of the reference dose, e.g., for a period of
at least about 2-42 days (e.g., 2-21 days) after stopping
posaconazole treatment. Accordingly, in various embodiments, the
methods include treating, or prescribing the first treatment to
begin, with a therapeutically effective amount of a CYP3A4
substrate drug contraindicated for concomitant use with a strong
CYP3A4 inhibitor to a patient in need thereof. In some embodiments,
the patient has previously been treated with posaconazole. In some
embodiments, the patient is treated, or prescribed to be treated,
with a CYP3A4 substrate drug at a dose which is no more than about
50% of the reference dose for at least about 2-42 days (e.g., 2-21
days) after discontinuation of the posaconazole regimen.
[0011] In various embodiments, the present disclosure provides for
methods of treating patients, or prescribing treatment for
patients, having a disease or condition selected from the group
consisting of schizophrenia in adults and adolescents (13 to 17
years), depressive episodes associated with Bipolar I Disorder
(bipolar depression) in adults, monotherapy or adjunctive therapy
with lithium or valproate, chronic angina, cystic fibrosis in
patients 6 years and older who are homozygous for the F508del
mutation in the CFTR gene, chronic lymphocytic leukemia in patients
with 17p deletion, who have received at least one prior therapy,
unresectable or metastatic liposarcoma or leiomyosarcoma in
patients who received a prior anthracycline-containing regimen,
advanced or metastatic breast cancer in postmenopausal women with
hormone receptor (HR)-positive, human epidermal growth factor
receptor 2 (HER2)-negative advanced or metastatic breast cancer,
negative advanced or metastatic breast cancer in combination with
an aromatase inhibitor for postmenopausal women, Duchenne muscular
dystrophy (DMD), secondary hyperparathyroidism (HPT) in patients
with chronic kidney disease (CKD) on dialysis, hypercalcemia in
patients with parathyroid carcinoma or in patients with primary HPT
for who parathyroidectomy would be indicated on the basis of serum
calcium levels, but who are unable to undergo parathyroidectomy,
hallucinations and delusions associated with Parkinson's disease
psychosis, schizophrenia, acute manic or mixed episodes associated
with bipolar I disorder, chronic hepatitis C (CHC) infection as a
component of a combination antiviral treatment regimen with
peginterferon alfa and ribavirin in HCV genotype 1 infected
subjects with compensated liver disease, postmenopausal women with
advanced hormone receptor-positive, HER2-negative breast cancer
(advanced HR+ BC), e.g., in combination with exemestane after
failure of treatment with letrozole or anastrozole, progressive
neuroendocrine tumors of pancreatic origin (PNET), progressive,
well-differentiated, non-functional neuroendocrine tumors (NET) of
gastrointestinal (GI) or lung origin that are unresectable, locally
advanced or metastatic, advanced renal cell carcinoma (RCC), e.g.,
after failure of treatment with sunitinib or sorafenib, renal
angiomyolipoma and tuberous sclerosis complex (TSC), not requiring
immediate surgery, TSC in patients who have subependymal giant cell
astrocytoma (SEGA) that require therapeutic intervention but are
not candidates for surgical resection, type 2 diabetes mellitus in
adults as an adjunct to diet and exercise to improve glycemic
control, major depressive disorder (MDD), thrombotic cardiovascular
events (e.g., cardiovascular death, myocardial infarction, or
stroke) in patients with acute coronary syndrome (ACS), stroke and
systemic embolism in patients with nonvalvular atrial fibrillation,
deep vein thrombosis (DVT), which may lead to pulmonary embolism
(PE) in patients who have undergone hip or knee replacement
surgery, DVT, PE, recurrent DVT and PE following initial therapy,
moderate to severe active rheumatoid arthritis in patients who have
had inadequate response or tolerance to methotrexate, acute
migraine with or without aura, chronic phase and accelerated phase
Philadelphia chromosome positive chronic myeloid leukemia (Ph+
CIVIL) in newly diagnosed patients or in patients resistant to or
intolerant to prior therapy that included imatinib, atrial
fibrillation (AF) in patients with a history of paroxysmal or
persistant AF or atrial flutter (AFK), who are in sinus rhythm or
will be cardioverted, asthma in patients aged 4 years and older,
airflow obstruction and reducing exacerbations in patients with
chronic obstructive pulmonary disease, erectile dysfunction (ED),
benign prostatic hyperplasia (BPH), pulmonary arterial hypertension
(PAH) (WHO Group 1) to improve exercise ability, gout flares,
Familial Mediterranean fever, antiretroviral therapy, anxiety
disorders, panic disorders, seizures, insomnia, hypertension,
cardiovascular disease, hyperlipidemia, cancer, such as primary
kidney cancer, advanced primary liver cancer, radioactive iodine
resistant advanced thyroid carcinoma, renal cell carcinoma,
imatinib-resistant gastrointestinal stromal tumor, mantle cell
lymphoma in patients who have received at least one prior therapy,
chronic lymphocytic leukemia/small lymphocytic lymphoma, chronic
lymphocytic leukemia/small lymphocytic lymphoma with 17p deletion,
Waldenstrom's macroglobulinemia, marginal zone lymphoma who require
systemic therapy and have received at least one prior
anti-CD20-based therapy, unresectable or metastatic melanoma with a
BRAF V600E or V600K mutation, allergies, transplantation,
hormone-refractory metastatic prostate cancer previously treated
with a docetaxel-containing treatment regimen, hormone-refractory
metastatic prostate cancer previously treated with a
docetaxel-containing treatment regimen, treatment of clinically
significant hypervolemic and euvolemic hyponatremia, including
patients with heart failure and Syndrome of Inappropriate
Antidiuretic Hormone (SIADH), prevention of acute and delayed
nausea and vomiting associated with initial and repeat courses of
highly emetogenic cancer chemotherapy (HEC) including high-dose
cisplatin, prevention of delayed nausea and vomiting associated
with initial and repeat courses of moderately emetogenic cancer
chemotherapy (MEC), over-active bladder with symptoms of urge
urinary incontinence, urgency, and urinary frequency, metastatic
non-small cell lung cancer (NSCLC) whose tumors have epidermal
growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R)
substitution mutations as detected by an FDA-approved test
receiving first-line, maintenance, or second or greater line
treatment after progression, locally advanced, unresectable or
metastatic pancreatic cancer, in combination with gemcitabine,
HER2-positive, metastatic breast cancer who previously received
trastuzumab and a taxane, separately or in combination in patients
who have either: received prior therapy for metastatic disease or
developed disease recurrence during or within six months of
completing adjuvant therapy, chronic, accelerated, or blast phase
Ph+ chronic myelogenous leukemia (CIVIL) in adults with resistance
or intolerance to prior therapy, gastrointestinal stromal tumor
(GIST) after disease progression on or intolerance to imatinib
mesylate, advanced renal cell carcinoma (RCC), progressive,
well-differentiated pancreatic neuroendocrine tumors (pNET) in
patients with unresectable locally advanced or metastatic disease,
CCR5-tropic HIV-1 infection in patients 2 years of age and older
weighing at least 10 kg in combination with other antiretroviral
agents, advanced renal cell carcinoma, advanced soft tissue sarcoma
who have received prior chemotherapy, manic and mixed episodes
associated with Bipolar I, Major Depressive Disorder, irritability
associated with Autistic Disorder, Tourette's disorder, agitation
associated with schizophrenia or bipolar mania, advanced renal cell
carcinoma after failure of one prior systemic therapy, to improve
glycemic control in adults with type 2 diabetes mellitus (T2DM) who
have inadequate control with dapagliflozin or who are already
treated with dapagliflozin and saxagliptin, progressive, metastatic
medullary thyroid cancer (MTC), advanced renal cell carcinoma (RCC)
who have received prior anti-angiogenic therapy, chronic phase,
accelerated phase, or blast phase chronic myeloid leukemia (CML) or
Ph+ ALL in adults for whom no other tyrosine kinase inhibitor (TKI)
therapy is indicated, T315I-positive CIVIL (chronic phase,
accelerated phase, or blast phase) or T315I-positive Philadelphia
chromosome in adults, positive acute lymphoblastic leukemia (Ph+
ALL), invasive aspergillosis, invasive mucormycosis, to reduce
low-density lipoprotein cholesterol (LDL-C), total cholesterol
(TC), apolipoprotein B (apo B), and non-high density lipoprotein
cholesterol (non-HDL-C) in patients with homozygous familial
hypercholesterolemia (HoFH), schizophrenia in adults, hormone
receptor (HR)-positive, human epidermal growth factor receptor 2
(HER2)-negative advanced or metastatic breast cancer in combination
with an aromatase inhibitor as initial endocrine based therapy in
postmenopausal women, or fulvestrant in women with disease
progression following endocrine therapy, Major Depressive Disorder
(MDD), suppression of motor and phonic tics in patients with
Tourette's Disorder who have failed to respond satisfactorily to
standard treatment, treatment of multiple myeloma in patients who
have received at least two prior therapies including lenalidomide
and a proteasome inhibitor and have demonstrated disease
progression on or within 60 days of completion of the last therapy,
non-small cell lung cancer (NSCLC) whose disease has not progressed
after four cycles of platinum-based first-line chemotherapy,
locally advanced or metastatic NSCLC after failure of at least one
prior chemotherapy regimen, locally advanced, unresectable or
metastatic pancreatic cancer, overactive bladder with symptoms of
urge urinary incontinence, urgency, and urinary frequency, advanced
renal cell carcinoma (RCC) after failure of treatment with
sunitinib or sorafenib, subependymal giant cell astrocytoma (SEGA)
associated with tuberous sclerosis (TS) who require therapeutic
intervention but are not candidates for curative surgical
resection, renal angiomyolipoma, tuberous sclerosis complex,
hormone receptor (HR)-positive, human epidermal growth factor
receptor 2 (HER2)-negative advanced or metastatic breast cancer
with disease progression following endocrine therapy in women in
combination with fulvestrant, as monotherapy for the treatment of
adult patients with HRpositive, HER2-negative advanced or
metastatic breast cancer with disease progression following
endocrine therapy and prior chemotherapy in the metastatic setting,
cystic fibrosis (CF) in patients age 2 years and older who have one
mutation in the CFTR gene that is responsive to ivacaftor based on
clinical and/or in vitro assay data, deleterious or suspected
deleterious germline BRCA-mutated advanced ovarian cancer in adult
patients who have been treated with three or more prior lines of
chemotherapy, intermediate or high-risk myelofibrosis, including
primary myelofibrosis, post-polycythemia vera myelofibrosis and
post-essential thrombocythemia myelofibrosis, polycythemia vera
patients who have had an inadequate response to or are intolerant
of hydroxyurea, as an adjunctive therapy to antidepressants for the
treatment of major depressive disorder (MDD), schizophrenia, cystic
fibrosis (CF) patients aged 12 years and older who are homozygous
for the F508del mutation or who have at least one mutation in the
cystic fibrosis transmembrane conductance regulator (CFTR) gene
that is responsive to tezacaftor/ivacaftor based on in vitro data
and/or clinical evidence, metastatic colorectal cancer (CRC)
patients who have been previously treated with fluoropyrimidine-,
oxaliplatin- and irinotecan-based chemotherapy, an antiVEGF
therapy, and, if RAS wild-type, an anti-EGFR therapy, locally
advanced, unresectable or metastatic gastrointestinal stromal tumor
(GIST) patients who have been previously treated with imatinib
mesylate and sunitinib malate, hepatocellular carcinoma (HCC) who
have been previously treated with sorafenib, chronic HCV genotype 1
or 3 infection with sofosbuvir and with or without ribavirin,
metastatic non-small cell lung cancer (NSCLC) in patients whose
tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as
detected by an FDA-approved test, opioid induced constipation (OIC)
in adult patients with chronic non-cancer pain, including patients
with chronic pain related to prior cancer or its treatment who do
not require frequent (e.g., weekly) opioid dosage escalation,
unresectable or metastatic melanoma in patients with BRAF V600E
mutation as detected by an FDA-approved test, in combination with
trametinib, for the treatment of unresectable or metastatic
melanoma in patients with BRAF V600E or V600K mutations as detected
by an FDA-approved test, melanoma in patients with BRAF V600E or
V600K mutations, as detected by an FDA-approved test, and
involvement of lymph node(s), following complete resection,
metastatic non-small cell lung cancer (NSCLC) in patients with BRAF
V600E mutation as detected by an FDA-approved test, locally
advanced or metastatic anaplastic thyroid cancer (ATC) in patients
with BRAF V600E mutation and with no satisfactory locoregional
treatment options, and with or without ribavirin for treatment of
chronic HCV genotypes 1 or 4 infection in adults. In some
embodiments, the methods include treating the disease or condition
with a CYP3A4 substrate drug which is contraindicated for
concomitant use with a strong CYP3A4 inhibitor, wherein the patient
is also in need of treatment with a strong CYP3A4 inhibitor (i.e.,
posaconazole). In some embodiments, the methods include (a)
delaying a first treatment of the CYP3A4 substrate drug for at
least about 2-21 days after stopping posaconazole; and then (b)
treating, or prescribing a first treatment, with the CYP3A4
substrate drug. In other embodiments, the methods include (a)
delaying a first treatment of the CYP3A4 substrate drug for at
least about 2-21 days after stopping administration of the
posaconazole regimen, and then (b) treating or prescribing a first
treatment the CYP3A4 substrate drug at a dose which is less than or
equal to about 50% of the reference dose for at least about 2-21
days after stopping administration of the posaconazole regimen.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 shows mean (.+-.standard error) plasma posaconazole
concentrations in normal-weight subjects, and in obese subjects
during the period of posaconazole administration and after
disconcontinuation. See Table 2 for kinetic analysis.
[0013] FIG. 2 shows mean plasma lurasidone concentrations in
normal-weight subjects (FIGS. 2A and 2B) and in obese subjects
(FIGS. 2C and 2D). FIGS. 2A and 2C show the 72-hour duration of the
study with a logarithmic concentration axis. FIGS. 2B and 2D show
the first 24 hours after dosage with a linear concentration axis.
(Data for Days 20 and 26 is not shown).
[0014] FIG. 3 shows the arithmetic mean (.+-.standard error) ratio
of lurasidone AUC during and after posaconazole dosage divided by
the AUC in the baseline control condition in normal-weight and
obese subject groups. At all time points, the ratios were
significantly different from 1.0.
[0015] FIG. 4 shows the relation of plasma posaconazole
concentration (X-axis) to Lurasidone AUC (Y-axis). Solid line
represents the function of best fit as determined by linear
regression analysis. The fitted function is: Y=2.38
X.sup.0.58+110.6.
[0016] FIG. 5 shows the mean (.+-.SD) and log-transformed plasma
posaconazole concentrations in normal-weight subjects and obese
subjects during the period of posaconazole administration and after
discontinuation. FIG. 5A shows a linear concentration axis. FIG. 5B
shows a logarithmic concentration axis.
[0017] FIG. 6 shows the mean (.+-.SD) plasma ranolazine
concentrations in normal-weight subjects (FIG. 6A) and obese
subjects (FIG. 6B) alone (day 1), with posaconazole
coadministration (day 15), and after posaconazole discontinuation
(days 18-29). See Table 10 for kinetic analysis. Top is linear
concentration axes. Right is logarithmic concentration axes.
[0018] FIG. 7 shows the geometric mean ratios (GMR) and 90% CI of
ranolazine AUC (FIG. 7A) and C.sub.max (FIG. 7B) relative to day 1.
GMR=1.5 line refers to the levels observed during ranolazine
coadministration with diltiazem in preapproval studies. AUC
indicates area under the concentration-time curve; C.sub.max, peak
concentration.
DETAILED DESCRIPTION
[0019] All documents, including patents, applications, and
non-patent publications cited herein are incorporated herein in
their entireties for all purposes.
[0020] As used herein, the term "about" refers to an amount
somewhat more or less than the stated parameter value, for example
plus or minus five or ten percent of the object that "about"
modifies, or as one of skill in the art would recognize from the
context (e.g., approximately 50% of the interval between values).
The term "about" also includes the value referenced. For example, a
BMI of about 40 includes 40, as well as values somewhat below or
above 40.
[0021] As used herein, the term "patient" refers to a human
subject. In some embodiments, the patient can be a male or a
female. In some embodiments, the patient can be an adult, or a
pediatric patient.
[0022] As used herein "treating or "prescribing" as it pertains to
the CYP3A4 substrate drug during the 2-21 day period after ceasing
posaconazole treatment, refers to the overall therapeutic regimen
of the CYP3A4 substrate drug. For example, a patient may be
prescribed or administered (including self-administering) a reduced
dose of the CYP3A4 substrate drug (e.g., no more than about 50% of
the reference dose of the CYP3A4 substrate drug) during this
period. In some embodiments, the patient would not be administered,
or would, in the physician's prescribed dosing regimen, be advised
not to take the CYP3A4 substrate drug during the 2-21 day period;
afterwards, the patient could (or would be prescribed to) resume
taking e.g., the reference amount of the CYP3A4 substrate drug.
[0023] As used herein, the terms "treating," "treatment" and
"treat" include (i) preventing a particular disease or disorder
from occurring in a subject who may be predisposed to the disease
or disorder but has not yet been diagnosed as having it; (ii)
curing, treating, or inhibiting the disease, i.e., arresting its
development; or (iii) ameliorating the disease by reducing or
eliminating symptoms, conditions, and/or by causing regression of
the disease. In some embodiments, "treating," "treatment" and
"treat" may include administering a therapeutically effective
regimen as defined herein.
[0024] As used herein, a "therapeutically effective regimen" refers
to a treatment regimen of a duration and dosage sufficient to treat
a disease or condition for which a drug is prescribed.
[0025] As used herein, a "patient" refers to human subject that has
an indication amendable to treatment with posaconazole and is also
in need of treatment with a CYP3A4 substrate drug. For example, the
patient, prior to being treated with or prescribed posaconazole,
can simultaneously have a first indication amendable to treatment
with posaconazole and a second indication amendable to treatment
the CYP3A4 substrate drug. In some such embodiments, the patient is
first treated with posaconazole, and then, after stopping the
posaconazole regimen, the patient is switched to a treatment
described herein for the CYP3A4 substrate drug. In other
embodiments, the patient, while being treated with posaconazole,
develops an indication amendable to treatment with a CYP3A4
substrate drug. In some such embodiments, after stopping the
posaconazole regimen, the patient is switched to a treatment
descried herein for the CYP3A4 substrate drug. As used herein, a
"patient" does not include a subject that, at some point after
stopping posaconazole treatment, subsequently develops an
indication which is amendable to treatment with a CYP3A4 substrate
drug.
[0026] As used herein, a "patient treated with posaconazole" or a
"patient previously on posaconazole" refers to a patient having an
indication which was amenable to treatment with posaconazole.
[0027] As used herein, the term "normal baseline C.sub.max" refers
to the average C.sub.max of a drug measured at the same dosage in
an otherwise identical patient which was not previously treated
with the strong CYP3A4 inhibitor (e.g., posaconazole). For example,
when the CYP3A4 substrate drug is ranolazine, the "normal baseline
C.sub.max" of ranolazine refers to the average C.sub.max of
ranolazine measured at the same dosage of ranolazine in an
otherwise identical patient which was not previously treated with
the strong CYP3A4 inhibitor (e.g., posaconazole). As another
example, when the CYP3A4 substrate drug is lurasidone, the "normal
baseline C.sub.max" of lurasidone refers to the average C.sub.max
of lurasidone measured at the same dosage of lurasidone in an
otherwise identical patient which was not previously treated with
the strong CYP3A4 inhibitor (e.g., posaconazole). As another
example, when the CYP3A4 substrate drug is tadalafil, the "normal
baseline C.sub.max" of tadalafil refers to the average C.sub.max of
tadalafil measured at the same dosage of tadalafil in an otherwise
identical patient which was not previously treated with the strong
CYP3A4 inhibitor (e.g., posaconazole).
[0028] As used herein, the term "normal baseline AUC" refers to the
average AUC of a drug measured at the same dosage in an otherwise
identical patient which was not previously treated with the strong
CYP3A4 inhibitor (e.g., posaconazole). For example, when the CYP3A4
substrate drug is ranolazine, the "normal baseline AUC" of
ranolazine refers to the average AUC of ranolazine measured at the
same dosage of ranolazine in an otherwise identical patient which
was not previously treated with the strong CYP3A4 inhibitor (e.g.,
posaconazole). As another example, when the CYP3A4 substrate drug
is lurasidone, the "normal baseline AUC" of lurasidone refers to
the average AUC of lurasidone measured at the same dosage of
lurasidone in an otherwise identical patient which was not
previously treated with the strong CYP3A4 inhibitor (e.g.,
posaconazole). As another example, when the CYP3A4 substrate drug
is tadalafil, the "normal baseline AUC" of tadalafil refers to the
average AUC of tadalafil measured at the same dosage of tadalafil
in an otherwise identical patient which was not previously treated
with the strong CYP3A4 inhibitor (e.g., posaconazole).
[0029] As used herein, "normal," "reference," or other derivations
or variations thereof refers to a non-obese state in a person who
can have at least one of the following characteristics: BMI less
than about 35, % IBW less than about 150%, waist size less than
about 42, % body fat less than about 40%, % android body fat less
than about 40%, % gynoid body fat less than about 40%, and total
body fat less than about 40 kg. Unless otherwise modified "normal
metabolizer" also means an extensive CYP3A4 metabolizer.
[0030] As used herein, a "reference dose" refers to the dosage of a
particular CYP3A4 substrate drug, as indicated on the manufacture's
FDA-approved label, prescribed for an identical patient not
previously treated with the strong CYP3A4 inhibitor (e.g.,
posaconazole).
[0031] Any reference to a CYP3A4 substrate drug herein also
encompasses all of the pharmaceutically acceptable isomers (e.g.,
stereoisomers), solvates, hydrates, polymorphs, and prodrugs (e.g.,
esters and phosphates). For example, a reference to solifenacin
herein also includes its pharmaceutically acceptable salts, such as
a succinate salt. As another example, a reference to naloxegol
herein also includes its pharmaceutically acceptable salts, such as
an oxalate salt.
[0032] As used herein, "stereoisomer" is a general term used for
all isomers of individual molecules that differ only in the
orientation of their atoms in space. The term stereoisomer includes
mirror image isomers (enantiomers), mixtures of mirror image
isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z)
isomers, and isomers of compounds with more than one chiral center
that are not mirror images of one another (diastereoisomers). The
CYP3A4 substrate drugs of the present invention may have asymmetric
centers and occur as racemates, racemic mixtures, individual
diastereoisomers, or enantiomers, or may exist as geometric
isomers, with all isomeric forms of said compounds being included
in the present invention. Further, the CYP3A4 substrate drug may
include any ratio for a mixture of stereoisomers, e.g., from about
1:99 to about 99:1 including all ratios and subranges in between,
such as about 95:5, about 90:10, about 85:15, about 80:20, about
75:25, about 70:30, about 65:35, about 60:40, about 55:45, about
50:50, about 45:55, about 40:60, about 35:65, about 30:70, about
25:75, about 20:80, about 15:85, about 10:90, and about 95:5.
[0033] The present disclosure also encompasses combinations of the
CYP3A4 substrate drugs described herein. Therefore, in accordance
of any of the embodiments of the present disclosure, a patient may
be treated with more than one CYP3A4 substrate drug, such as
lurasidone and ranolazine.
[0034] Disclosed herein are methods of treating, or prescribing
treatment for, a patient with a CYP3A4 substrate drug
contraindicated for concomitant administration with a strong CYP3A4
inhibitor, wherein the patient was previously treated with
posaconazole, particularly when patients having one or more of the
physiological characteristics described herein are subsequently
treated with a CYP3A4 substrate drug. That is, the disclosure
provides for methods of treating different patient
populations--e.g., "normal" patients, obese patients, and/or
intermediate or worse (e.g., poor) CYP3A4 metabolizers--with a
CYP3A4 substrate drug contraindicated for concomitant
administration with a strong CYP3A4 inhibitor after said patient
has ceased posaconazole treatment. Methods of initiating treatment
with a CYP3A4 substrate drug intended to treat various conditions
or disorders in patients previously treated with posaconazole are
also described herein. The present disclosure also provides methods
of preventing or decreasing the risk of side effects associated
with overexposure to a CYP3A4 substrate drug in normal patients,
obese patients and/or patients with impaired CYP3A4 function (e.g.,
poor or intermediate CYP3A4 metabolizers) and who had previously
been treated with a posaconazole regimen prior to treating or
prescribing a CYP3A4 substrate drug to said patient. (including
those for treating conditions described herein).
[0035] In various embodiments, the present disclosure provides
methods for treating, or prescribing treatment for, a patient who
had been treated with a therapeutically effective posaconazole
regimen with a CYP3A4 substrate drug, after a "washout" period of
about 2-21 days after ceasing administration of posaconazole. This
washout period allows for the blood plasma concentrations of
posaconazole to be reduced to appropriate levels after which a
CYP3A4 substrate drug can be administered without creating an
elevated risk of serious side effects from the CYP3A4 substrate
drug. As described herein, the present Applicants have found that
CYP3A4 substrate drugs can be safely administrated to a patient
previously treated with posaconazole, by first treating, or
prescribing a first treatment, with the CYP3A4 substrate drug
(i.e., initiating the treatment with the CYP3A4 substrate drug)
following a "washout" period of about 2-21 days starting at the
time the patient has stopped posaconazole treatment. However, the
need for such a washout period has been hitherto unknown, as such
CYP3A4 substrate drugs are conventionally contraindicated for
concomitant administration with posaconazole. As also described
herein, in some embodiments the present Applicants have found that
instead of a washout period, the CYP3A4 substrate drug can
potentially be safely administrated to a patient previously treated
with posaconazole, at a dose which is no more than about 50% of the
reference dose of the CYP3A4 substrate drug for a period of about
2-21 days after ceasing the posaconazole treatment. Similarly, such
a dosing regime has been hitherto unknown.
[0036] Cytochrome P450 3A4 (CYP3A4) is an enzyme that modifies
small organic molecules, such as particular drugs (specifically
including drugs referred to herein as "CYP3A4 substrate drugs"), so
that the molecules are metabolized and eliminated from the body.
Some substances, termed "CYP3A4 inhibitors," reduce the activity of
the CYP3A4 enzyme, and therefore these CYP3A4 inhibitors can
increase the exposure of a patient to CYP3A4 substrate drugs.
Strong CYP3A4 inhibitors can deactivate CYP3A4 if administered in
an appropriate dose, which can result in excessive and potentially
dangerous blood plasma levels of a concomitantly administered
CYP3A4 substrate drugs. Consequently, concomitant administration of
CYP3A4 substrate drugs is contraindicated with strong CYP3A4
inhibitors.
[0037] As used herein, a "strong CYP3A4 inhibitor" refers to a drug
deemed so by the FDA and/or which causes at least about a 5-fold
increase in the AUC of a sensitive CYP3A4 substrate drug, or more
than about an 80% decrease in the clearance of a sensitive CYP3A4
substrate drug. The methods disclosed herein can be applied to
treat a patient with any CYP3A4 substrate drug which is
contraindicated for concomitant administration with any strong
CYP3A4 inhibitor, wherein the patient has been treated with a
strong CYP3A4 inhibitor, such as posaconazole.
[0038] Co-administration of posaconazole and CYP3A4 substrate drugs
known to prolong the QT.sub.c interval are contraindicated. The
presence of concomitant and clinically significant plasma levels of
posaconazole and such CYP3A4 substrate drugs can result in
significantly elevated levels of the CYP3A4 substrate drug, which
creates a risk of prolonging QT. Consequences of prolonged QT
include arrhythmias, rapid heartbeat, abnormal heart rhythm, heart
palpitations, dizziness, lightheadedness, sudden fainting, seizure,
torsades de pointes, and cardiac death.
[0039] For example, according to the drug label for posaconazole
(NOXAFIL.RTM. label, revised November 2015), patients are advised
not to co-administer specific CYP3A4 substrate drugs such as
serolimus, pimozide, quinidine, HMG-CoA reductase inhibitors, ergot
alkaloids, or drugs known to prolong the QT.sub.c interval and
cause cases of TdP, with posaconazole. The NOXAFIL.RTM. label also
warns that dose adjustments should be considered for concomitant
administration of posaconazole and other drugs metabolized by
CYP3A4 such as tacrolimus, cyclosporine, vinca alkaloids, and
calcium channel blockers. However, the drug label of posaconazole
does not recognize that any washout period or any stratification of
the patient populations are required after ceasing administration
of posaconazole and before initiating administration of a CYP3A4
substrate.
[0040] In some embodiments, the strong CYP3A4 inhibitor is
posaconazole (i.e., Noxafil, Posanol). Posaconazole is currently
formulated as an oral suspension solution (40 mg/mL), and
intravenous solution (18 mg/mL), and delayed release tablets (100
mg). According to the drug label (Merck & Co., Inc.,), current
recommended dosing levels for prophylaxis of invasive Aspergillus
and Candida infections by intraveneous injection or by
delayed-release tablet are 300 mg twice a day on the first day and
300 mg once a day thereafter, or 200 mg three times a day by oral
suspension. Current recommended dosing levels for treatment of
oropharyngeal candidiasis by oral suspension are 100 mg twice a day
on the first day and 100 mg once a day for 13 days. Current
recommended dosing levels for treatment of oropharyngeal
candidiasis refractory to itraconazole and/or fluconazole by oral
suspension is 400 mg twice a day.
[0041] In some embodiments, posaconazole can be indicated for the
treatment of fungal infections. In one embodiment, posaconazole can
be indicated for the treatment of infections caused by Candida,
e.g., oropharyngeal candidiasis. In one embodiment, posaconazole
can be indicated for the treatment of oropharyngeal candidiasis
which is refractory to itraconazole and/or fluconazole. In one
embodiment, posaconazole can be indicated for the treatment of
infections caused by Aspergillus. In one embodiment, posaconazole
can be indicated for the treatment of infections caused by
Zygomycetes. In some embodiments, posaconazole can be indicated for
the prophylaxis of Aspergillus or Candida infections, e.g., in
immunocompromised patients at high risk of developing such
infections, such as hematopoietic stem cell transplant (HSCT)
recipients with graft-versus-host disease (GVHD) or patients with
hematologic malignancies with prolonged neutropenia from
chemotherapy. In one embodiment, posaconazole can be indicated for
the treatment of zygomycosis. In one embodiment, posaconazole can
be indicated for the treatment of allergic bronchopulmonary
aspergillosis. In one embodiment, posaconazole can be indicated for
the treatment or prophylaxis of recurrent candidiasis for the
esophagus, secondary to HIV infections. In one embodiment,
posaconazole can be indicated for the treatment of Fusarium
infections mycosis. In one embodiment, posaconazole can be
indicated for the treatment of and chronic or cavitary necrotizing
pulmonary aspergillosis.
[0042] As used herein, a "CYP3A4 substrate drug" refers to any drug
which is primarily metabolized by the CYP3A4 enzyme which is
administered in any pharmaceutically acceptable formulation (e.g.
tablet, capsule, oral solution, injection, infusion, or delayed or
extended release formulations thereof). In some embodiments, the
CYP3A4 drug is lurasidone (Latuda). In some embodiments, the CYP3A4
is ranolazine (Ranexa). In some embodiments, the CYP3A4 substrate
drugs can include lumacaftor/ivacaftor (Orkambi). In some
embodiments, the CYP3A4 substrate drugs can include venetoclax
(Venclexta). In some embodiments, the CYP3A4 substrate drugs can
include trabectedin (Yondelis). In some embodiments, the CYP3A4
substrate drugs can include ribociclib succinate (Kisqali). In some
embodiments, the CYP3A4 substrate drugs can include deflazacort
(Emflaza). In some embodiments, the CYP3A4 substrate drugs can
include cinacalcet hydrochloride (Sensipar). In some embodiments,
the CYP3A4 substrate drugs can include pimavanserin tartrate
(Nuplazid). In some embodiments, the CYP3A4 substrate drugs can
include aripiprazole lauroxil (Aristada). In some embodiments, the
CYP3A4 substrate drugs can include cariprazine hydrochloride
(Vraylar). In some embodiments, the CYP3A4 substrate drugs can
include simeprevir sodium (Olysio). In some embodiments, the CYP3A4
substrate drugs can include everolimus (Afinitor, Afinitor Disperz,
Zortress). In some embodiments, the CYP3A4 substrate drugs can
include saxagliptin hydrochloride (Onglyza). In some embodiments,
the CYP3A4 substrate drugs can include saxagliptin/metformin
hydrochloride (Kombiglyze XR). In some embodiments, the CYP3A4
substrate drugs can include ticagrelor (Brilinta). In some
embodiments, the CYP3A4 substrate drugs can include vilazodone
hydrochloride (Viibryd). In some embodiments, the CYP3A4 substrate
drugs can include apixaban (Eliquis). In some embodiments, the
CYP3A4 substrate drugs can include tofacitinib citrate (Xeljanz).
In some embodiments, the CYP3A4 substrate drugs can include
eletriptan hydrobromide (Relpax). In some embodiments, the CYP3A4
substrate drugs can include nilotinib hydrochloride monohydrate
(Tasigna). In some embodiments, the CYP3A4 substrate drugs can
include dronedarone hydrochloride (Multaq). In some embodiments,
the CYP3A4 substrate drugs can include fluticasone
propionate/salmeterol xinafoate (Advair Diskus). In some
embodiments, the CYP3A4 substrate drugs can include rivaroxaban
(Xarelto). In some embodiments, the CYP3A4 substrate drugs can
include tadalafil (Cialis, Adcirca). In some embodiments, the
CYP3A4 substrate drugs can include colchicine (Colcrys). In some
embodiments, the CYP3A4 substrate drugs can include ibrutinib
(Imbruvica). In some embodiments, the CYP3A4 substrate drugs can
include cobimetinib (Cotellis). In some embodiments, the CYP3A4
substrate drugs can include cabazitaxel (Jevtana). In some
embodiments, the CYP3A4 substrate drugs can include tolvaptan
(Samsca). In some embodiments, the CYP3A4 substrate drugs can
include fosaprepitant dimeglumine (Emend). In some embodiments, the
CYP3A4 substrate drugs can include aprepitant (Emend). In some
embodiments, the CYP3A4 substrate drugs can include solifenacin
succinate (VESlcare). In some embodiments, the CYP3A4 substrate
drugs can include erlotinib hydrochloride (Tarceva). In some
embodiments, the CYP3A4 substrate drugs can include ado-trastuzumab
ematansine (Kadcycla). In some embodiments, the CYP3A4 substrate
drugs can include bosutinib monohydrate (Bosulif). In some
embodiments, the CYP3A4 substrate drugs can include sunitinib
malate (Sutent). In some embodiments, the CYP3A4 substrate drugs
can include fesoterodine fumarate (Toviaz). In some embodiments,
the CYP3A4 substrate drugs can include maraviroc (Selzentry). In
some embodiments, the CYP3A4 substrate drugs can include pazopanib
hydrochloride (Votrient). In some embodiments, the CYP3A4 substrate
drugs can include aripiprazole (Abilify). In some embodiments, the
CYP3A4 substrate drugs can include axitinib (Inlyta). In some
embodiments, the CYP3A4 substrate drugs can include
dapagliflozin/saxagliptin (Farxiga/Onglyza). In some embodiments,
the CYP3A4 substrate drugs can include cabozantinib S-malate
(Cabometyx). In some embodiments, the CYP3A4 substrate drugs can
include ponatinib hydrochloride (Iclusig). In some embodiments, the
CYP3A4 substrate drugs can include isavuconazonium sulfate
(Cresemba). In some embodiments, the CYP3A4 substrate drugs can
include lomitapide mesylate (Juxtapid). In some embodiments, the
CYP3A4 substrate drugs can include iloperidone (Fanapt). In some
embodiments, the CYP3A4 substrate drugs can include palbociclib
(Ibrance). In some embodiments, the CYP3A4 substrate drugs can
include levomilnacipran hydrochloride (Fetzima). In some
embodiments, the CYP3A4 substrate drugs can include pimozide
(Orap). In some embodiments, the CYP3A4 substrate drugs can include
pomalidomide (Pomalyst). In some embodiments, the CYP3A4 substrate
drugs can include abemaciclib (Verzenio). In some embodiments, the
CYP3A4 substrate drugs can include ivacaftor (Kalydeco). In some
embodiments, the CYP3A4 substrate drugs can include ruxolitinib
phosphate (Jakafi). In some embodiments, the CYP3A4 substrate drugs
can include brexpiprazole (Rexulti). In some embodiments, the
CYP3A4 substrate drugs can include ivacaftor/tezacaftor (Symdeko).
In some embodiments, the CYP3A4 substrate drugs can include
regorafenib (Stivarga). In some embodiments, the CYP3A4 substrate
drugs can include daclatasvir (Daklinza). In some embodiments, the
CYP3A4 substrate drugs can include crizotinib (Xalkori). In some
embodiments, the CYP3A4 substrate drugs can include naloxegol
oxalate (Movantik). In some embodiments, the CYP3A4 substrate drugs
can include dabrafenib (Tafinlar). In some embodiments, the CYP3A4
substrate drugs can include elbasvir and grazoprevir (Zepatier). In
some embodiments, the CYP3A4 substrate drugs can include olaparib
(Lynparza). Other non-limiting examples of CYP3A4 substrate drugs
include HIV protease inhibitors, such as amprenavir (Agenerase),
atazanavir (Reyataz), darunavir (Prezista), fosamprenavir (Lexiva,
Telzir), indinavir (Crixivan), lopinavir (Kaletra), nelfinavir
(Viracept), ritonavir (Norvir), saquinavir (Invirase, Forovase),
and tipranavir (Aptivus), benzodiazepines, such as alprazolam
(Xanax), clonazepam (Klonopin), and diazepam (Valium), calcium
channel blockers such as amlodipine (Norvasc), aranidipine
(Sapresta), azelnidipine (Calblock), barnidipine (HypoCa),
benidipine (Coniel), cilnidipine (Atelec, Cinalong, Siscard),
clevidipine (Cleviprex), isradipine (DynaCirc, Prescal),
efonidipine (Landel), felodipine (Plendil), lacidipine (Motens,
Lacipil), lercanidipine (Zanidip), manidipine (Calslot, Madipine),
nicardipine (Cardene, Carden SR), nifedipine (Procardia, Adalat),
nilvadipine (Nivadil), nimodipine (Nimotop), nisoldipine
(Baymycard, Sular, Syscor), nitrendipine (Cardif, Nitrepin,
Baylotensin), and pranidipine (Acalas), hydroxymethylglutaryl
coenzyme A-reductase inhibitors, such as atorvastatin (Lipitor,
Ator), lovastatin (Mevacor, Altocor, Altoprev), mevastatin
(Compactin) and simvastatin (Zocor, Lipex), antineoplastic drugs,
such as sorafenib (Nexavar) and sunitinib (Sutent), nonsedating
antihistamines, such as fexofenadine (Allegra), loratadine
(Claritin), desloratadine (Clarinex), cetirizine (Zyrtec),
levocetirizine (Xyza) and immunosuppressants, such as
cyclosporin.
[0043] In some embodiments, the CYP3A4 substrate drug used in the
methods disclosed herein can be any drug metabolized by CYP3A4, in
particular drugs metabolized by CYP3A4 and which are
contraindicated for use with strong CYP3A4 inhibitors or include
dose adjustment recommendations for concomitant administration with
CYP3A4 inhibitors. In some embodiments, the methods described
herein can be applied to any therapeutic regimen in which one or
more CYP3A4 substrate drug(s) described herein are used to treat a
patient previously on posaconazole, including therapeutic regimens
that entail treating a patient with a CYP3A4 substrate drug in
combination with other drugs.
[0044] In some embodiments, the CYP3A4 substrate drug can be
indicated for the treatment of disease or condition selected from
the group consisting of schizophrenia in adults and adolescents (13
to 17 years), depressive episodes associated with Bipolar I
Disorder (bipolar depression) in adults, as monotherapy or
adjunctive therapy with lithium or valproate, chronic angina,
cystic fibrosis in patients 6 years and older who are homozygous
for the F508del mutation in the CFTR gene, chronic lymphocytic
leukemia in patients with 17p deletion, who have received at least
one prior therapy, unresectable or metastatic liposarcoma or
leiomyosarcoma in patients who received a prior
anthracycline-containing regimen, advanced or metastatic breast
cancer in postmenopausal women with hormone receptor (HR)-positive,
human epidermal growth factor receptor 2 (HER2)-negative advanced
or metastatic breast cancer, negative advanced or metastatic breast
cancer in combination with an aromatase inhibitor for
postmenopausal women, Duchenne muscular dystrophy (DMD), secondary
hyperparathyroidism (HPT) in patients with chronic kidney disease
(CKD) on dialysis, hypercalcemia in patients with parathyroid
carcinoma or in patients with primary HPT for who parathyroidectomy
would be indicated on the basis of serum calcium levels, but who
are unable to undergo parathyroidectomy, hallucinations and
delusions associated with Parkinson's disease psychosis,
schizophrenia, acute manic or mixed episodes associated with
bipolar I disorder, chronic hepatitis C (CHC) infection as a
component of a combination antiviral treatment regimen with
peginterferon alfa and ribavirin in HCV genotype 1 infected
subjects with compensated liver disease, advanced hormone
receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in
postmenopausal women in combination with exemestane after failure
of treatment with letrozole or anastrozole, progressive
neuroendocrine tumors of pancreatic origin (PNET), progressive,
well-differentiated, non-functional neuroendocrine tumors (NET) of
gastrointestinal (GI) or lung origin that are unresectable, locally
advanced or metastatic, advanced renal cell carcinoma (RCC), e.g.,
after failure of treatment with sunitinib or sorafenib, renal
angiomyolipoma and tuberous sclerosis complex (TSC), not requiring
immediate surgery, TSC in patients who have subependymal giant cell
astrocytoma (SEGA) that require therapeutic intervention but are
not candidates for surgical resection, type 2 diabetes mellitus in
adults as an adjunct to diet and exercise to improve glycemic
control, major depressive disorder (MDD), thrombotic cardiovascular
events (e.g., cardiovascular death, myocardial infarction, or
stroke) in patients with acute coronary syndrome (ACS), stroke and
systemic embolism in patients with nonvalvular atrial fibrillation,
deep vein thrombosis (DVT), which may lead to pulmonary embolism
(PE) in patients who have undergone hip or knee replacement
surgery, DVT, PE, recurrent DVT and PE following initial therapy,
moderate to severe active rheumatoid arthritis in patients who have
had inadequate response or tolerance to methotrexate, acute
migraine with or without aura, chronic phase and accelerated phase
Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML)
in newly diagnosed patients or in patients resistant to or
intolerant to prior therapy that included imatinib, atrial
fibrillation (AF) in patients with a history of paroxysmal or
persistent AF or atrial flutter (AFK), who are in sinus rhythm or
will be cardioverted, asthma in patients aged 4 years and older,
airflow obstruction and reducing exacerbations in patients with
chronic obstructive pulmonary disease, erectile dysfunction (ED),
benign prostatic hyperplasia (BPH), pulmonary arterial hypertension
(PAH) (WHO Group 1) to improve exercise ability, gout flares,
Familial Mediterranean fever, antiretroviral therapy, anxiety
disorders, panic disorders, seizures, insomnia, hypertension,
cardiovascular disease, hyperlipidemia, cancer, such as primary
kidney cancer, advanced primary liver cancer, radioactive iodine
resistant advanced thyroid carcinoma, renal cell carcinoma,
imatinib-resistant gastrointestinal stromal tumor, mantle cell
lymphoma in patients who have received at least one prior therapy,
chronic lymphocytic leukemia/small lymphocytic lymphoma, chronic
lymphocytic leukemia/small lymphocytic lymphoma with 17p deletion,
Waldenstrom's macroglobulinemia, marginal zone lymphoma who require
systemic therapy and have received at least one prior
anti-CD20-based therapy, unresectable or metastatic melanoma with a
BRAF V600E or V600K mutation, allergies, transplantation,
hormone-refractory metastatic prostate cancer previously treated
with a docetaxel-containing treatment regimen, hormone-refractory
metastatic prostate cancer previously treated with a
docetaxel-containing treatment regimen, treatment of clinically
significant hypervolemic and euvolemic hyponatremia, including
patients with heart failure and Syndrome of Inappropriate
Antidiuretic Hormone (SIADH), prevention of acute and delayed
nausea and vomiting associated with initial and repeat courses of
highly emetogenic cancer chemotherapy (HEC) including high-dose
cisplatin, prevention of delayed nausea and vomiting associated
with initial and repeat courses of moderately emetogenic cancer
chemotherapy (MEC), over-active bladder with symptoms of urge
urinary incontinence, urgency, and urinary frequency, metastatic
non-small cell lung cancer (NSCLC) whose tumors have epidermal
growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R)
substitution mutations as detected by an FDA-approved test
receiving first-line, maintenance, or second or greater line
treatment after progression, locally advanced, unresectable or
metastatic pancreatic cancer, in combination with gemcitabine,
HER2-positive, metastatic breast cancer who previously received
trastuzumab and a taxane, separately or in combination in patients
who have either: received prior therapy for metastatic disease or
developed disease recurrence during or within six months of
completing adjuvant therapy, chronic, accelerated, or blast phase
Ph+ chronic myelogenous leukemia (CML) in adults with resistance or
intolerance to prior therapy, gastrointestinal stromal tumor (GIST)
after disease progression on or intolerance to imatinib mesylate,
advanced renal cell carcinoma (RCC), progressive,
well-differentiated pancreatic neuroendocrine tumors (pNET) in
patients with unresectable locally advanced or metastatic disease,
CCR5-tropic HIV-1 infection in patients 2 years of age and older
weighing at least 10 kg in combination with other antiretroviral
agents, advanced renal cell carcinoma, advanced soft tissue sarcoma
who have received prior chemotherapy, manic and mixed episodes
associated with Bipolar I, Major Depressive Disorder, irritability
associated with Autistic Disorder, Tourette's disorder, agitation
associated with schizophrenia or bipolar mania, advanced renal cell
carcinoma after failure of one prior systemic therapy, to improve
glycemic control in adults with type 2 diabetes mellitus (T2DM) who
have inadequate control with dapagliflozin or who are already
treated with dapagliflozin and saxagliptin, progressive, metastatic
medullary thyroid cancer (MTC), advanced renal cell carcinoma (RCC)
who have received prior anti-angiogenic therapy, chronic phase,
accelerated phase, or blast phase chronic myeloid leukemia (CML) or
Ph+ ALL in adults for whom no other tyrosine kinase inhibitor (TKI)
therapy is indicated, T315I-positive CML (chronic phase,
accelerated phase, or blast phase) or T315I-positive Philadelphia
chromosome in adults, positive acute lymphoblastic leukemia (Ph+
ALL), invasive aspergillosis, invasive mucormycosis, to reduce
low-density lipoprotein cholesterol (LDL-C), total cholesterol
(TC), apolipoprotein B (apo B), and non-high density lipoprotein
cholesterol (non-HDL-C) in patients with homozygous familial
hypercholesterolemia (HoFH), schizophrenia in adults, hormone
receptor (HR)-positive, human epidermal growth factor receptor 2
(HER2)-negative advanced or metastatic breast cancer in combination
with an aromatase inhibitor as initial endocrine based therapy in
postmenopausal women, or fulvestrant in women with disease
progression following endocrine therapy, Major Depressive Disorder
(MDD), suppression of motor and phonic tics in patients with
Tourette's Disorder who have failed to respond satisfactorily to
standard treatment, and treatment of multiple myeloma in patients
who have received at least two prior therapies including
lenalidomide and a proteasome inhibitor and have demonstrated
disease progression on or within 60 days of completion of the last
therapyallergies, transplantation, hormone-refractory metastatic
prostate cancer previously treated with a docetaxel-containing
treatment regimen, hormone-refractory metastatic prostate cancer
previously treated with a docetaxel-containing treatment regimen,
treatment of clinically significant hypervolemic and euvolemic
hyponatremia, including patients with heart failure and Syndrome of
Inappropriate Antidiuretic Hormone (SIADH), prevention of acute and
delayed nausea and vomiting associated with initial and repeat
courses of highly emetogenic cancer chemotherapy (HEC) including
high-dose cisplatin, prevention of delayed nausea and vomiting
associated with initial and repeat courses of moderately emetogenic
cancer chemotherapy (MEC), over-active bladder with symptoms of
urge urinary incontinence, urgency, and urinary frequency,
metastatic non-small cell lung cancer (NSCLC) whose tumors have
epidermal growth factor receptor (EGFR) exon 19 deletions or exon
21 (L858R) substitution mutations as detected by an FDA-approved
test receiving first-line, maintenance, or second or greater line
treatment after progression, locally advanced, unresectable or
metastatic pancreatic cancer, in combination with gemcitabine,
HER2-positive, metastatic breast cancer who previously received
trastuzumab and a taxane, separately or in combination in patients
who have either: received prior therapy for metastatic disease or
developed disease recurrence during or within six months of
completing adjuvant therapy, chronic, accelerated, or blast phase
Ph+ chronic myelogenous leukemia (CIVIL) in adults with resistance
or intolerance to prior therapy, gastrointestinal stromal tumor
(GIST) after disease progression on or intolerance to imatinib
mesylate, advanced renal cell carcinoma (RCC), progressive,
well-differentiated pancreatic neuroendocrine tumors (pNET) in
patients with unresectable locally advanced or metastatic disease,
CCR5-tropic HIV-1 infection in patients 2 years of age and older
weighing at least 10 kg in combination with other antiretroviral
agents, advanced renal cell carcinoma, advanced soft tissue sarcoma
who have received prior chemotherapy, manic and mixed episodes
associated with Bipolar I, Major Depressive Disorder, irritability
associated with Autistic Disorder, Tourette's disorder, agitation
associated with schizophrenia or bipolar mania, advanced renal cell
carcinoma after failure of one prior systemic therapy, to improve
glycemic control in adults with type 2 diabetes mellitus (T2DM) who
have inadequate control with dapagliflozin or who are already
treated with dapagliflozin and saxagliptin, progressive, metastatic
medullary thyroid cancer (MTC), advanced renal cell carcinoma (RCC)
who have received prior anti-angiogenic therapy, chronic phase,
accelerated phase, or blast phase chronic myeloid leukemia (CML) or
Ph+ ALL in adults for whom no other tyrosine kinase inhibitor (TKI)
therapy is indicated, T315I-positive CIVIL (chronic phase,
accelerated phase, or blast phase) or T315I-positive Philadelphia
chromosome in adults, positive acute lymphoblastic leukemia (Ph+
ALL), invasive aspergillosis, invasive mucormycosis, to reduce
low-density lipoprotein cholesterol (LDL-C), total cholesterol
(TC), apolipoprotein B (apo B), and non-high density lipoprotein
cholesterol (non-HDL-C) in patients with homozygous familial
hypercholesterolemia (HoFH), schizophrenia in adults, hormone
receptor (HR)-positive, human epidermal growth factor receptor 2
(HER2)-negative advanced or metastatic breast cancer in combination
with an aromatase inhibitor as initial endocrine based therapy in
postmenopausal women, or fulvestrant in women with disease
progression following endocrine therapy, Major Depressive Disorder
(MDD), suppression of motor and phonic tics in patients with
Tourette's Disorder who have failed to respond satisfactorily to
standard treatment, treatment of multiple myeloma in patients who
have received at least two prior therapies including lenalidomide
and a proteasome inhibitor and have demonstrated disease
progression on or within 60 days of completion of the last therapy,
non-small cell lung cancer (NSCLC) whose disease has not progressed
after four cycles of platinum-based first-line chemotherapy,
locally advanced or metastatic NSCLC after failure of at least one
prior chemotherapy regimen, locally advanced, unresectable or
metastatic pancreatic cancer, overactive bladder with symptoms of
urge urinary incontinence, urgency, and urinary frequency, advanced
renal cell carcinoma (RCC) after failure of treatment with
sunitinib or sorafenib, subependymal giant cell astrocytoma (SEGA)
associated with tuberous sclerosis (TS) who require therapeutic
intervention but are not candidates for curative surgical
resection, renal angiomyolipoma, tuberous sclerosis complex,
hormone receptor (HR)-positive, human epidermal growth factor
receptor 2 (HER2)-negative advanced or metastatic breast cancer
with disease progression following endocrine therapy in women in
combination with fulvestrant, as monotherapy for the treatment of
adult patients with HRpositive, HER2-negative advanced or
metastatic breast cancer with disease progression following
endocrine therapy and prior chemotherapy in the metastatic setting,
cystic fibrosis (CF) in patients age 2 years and older who have one
mutation in the CFTR gene that is responsive to ivacaftor based on
clinical and/or in vitro assay data, deleterious or suspected
deleterious germline BRCA-mutated advanced ovarian cancer in adult
patients who have been treated with three or more prior lines of
chemotherapy, intermediate or high-risk myelofibrosis, including
primary myelofibrosis, post-polycythemia vera myelofibrosis and
post-essential thrombocythemia myelofibrosis, polycythemia vera
patients who have had an inadequate response to or are intolerant
of hydroxyurea, as an adjunctive therapy to antidepressants for the
treatment of major depressive disorder (MDD), schizophrenia, cystic
fibrosis (CF) patients aged 12 years and older who are homozygous
for the F508del mutation or who have at least one mutation in the
cystic fibrosis transmembrane conductance regulator (CFTR) gene
that is responsive to tezacaftor/ivacaftor based on in vitro data
and/or clinical evidence, metastatic colorectal cancer (CRC)
patients who have been previously treated with fluoropyrimidine-,
oxaliplatin- and irinotecan-based chemotherapy, an antiVEGF
therapy, and, if RAS wild-type, an anti-EGFR therapy, locally
advanced, unresectable or metastatic gastrointestinal stromal tumor
(GIST) patients who have been previously treated with imatinib
mesylate and sunitinib malate, hepatocellular carcinoma (HCC) who
have been previously treated with sorafenib, chronic HCV genotype 1
or 3 infection with sofosbuvir and with or without ribavirin,
metastatic non-small cell lung cancer (NSCLC) patients whose tumors
are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected
by an FDA-approved test, opioid induced constipation (OIC) in adult
patients with chronic non-cancer pain, including patients with
chronic pain related to prior cancer or its treatment who do not
require frequent (e.g., weekly) opioid dosage escalation,
unresectable or metastatic melanoma in patients with BRAF V600E
mutation as detected by an FDA-approved test, in combination with
trametinib, unresectable or metastatic melanoma in patients with
BRAF V600E or V600K mutations as detected by an FDA-approved test,
adjuvant treatment of patients with melanoma in patients BRAF V600E
or V600K mutations, as detected by an FDA-approved test, and
involvement of lymph node(s), following complete resection,
metastatic non-small cell lung cancer (NSCLC) in patients with BRAF
V600E mutation as detected by an FDA-approved test, locally
advanced or metastatic anaplastic thyroid cancer (ATC) in patients
with BRAF V600E mutation and with no satisfactory locoregional
treatment options, and with or without ribavirin for treatment of
chronic HCV genotypes 1 or 4 infection in adults.
[0045] In some embodiments, the CYP3A4 substrate drug can be
indicated for the treatment of schizophrenia in adults and
adolescents (13 to 17 years), depressive episodes associated with
Bipolar I Disorder (bipolar depression) in adults, as monotherapy
or as adjunctive therapy with lithium or valproate.
[0046] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of chronic angina.
[0047] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of cystic fibrosis, e.g., in patients 6
years and older who are homozygous for the F508del mutation in the
CFTR gene.
[0048] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of chronic lymphocytic leukemia, e.g.,
in patients with 17p deletion, who have received at least one prior
therapy.
[0049] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of unresectable or metastatic
liposarcoma or leiomyosarcoma, e.g., in patients who received a
prior anthracycline-containing regimen.
[0050] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of advanced or metastatic breast
cancer, e.g., in postmenopausal women with hormone receptor
(HR)-positive, human epidermal growth factor receptor 2
(HER2)-negative advanced or metastatic breast cancer. In a further
embodiment, the CYP3A4 substrate drug can be indicated for a
treatment of negative advanced or metastatic breast cancer in
postmenopausal women e.g., in combination with an aromatase
inhibitor as initial endocrine-based therapy.
[0051] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of Duchenne muscular dystrophy
(DMD).
[0052] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of secondary hyperparathyroidism (HPT),
e.g., in patients with chronic kidney disease (CKD) on dialysis. In
one embodiment, the CYP3A4 substrate drug can be indicated for the
treatment of hypercalcemia, e.g., in patients with parathyroid
carcinoma. In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of hypercalcemia, e.g., in patients
with primary HPT for who parathyroidectomy would be indicated on
the basis of serum calcium levels, but who are unable to undergo
parathyroidectomy.
[0053] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of hallucinations and delusions
associated with Parkinson's disease psychosis.
[0054] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of schizophrenia.
[0055] In one embodiment, the CYP3A4 substrate drug can be
indicated for the acute treatment of manic or mixed episodes
associated with bipolar I disorder.
[0056] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of chronic hepatitis C (CHC) infection,
e. g., as a component of a combination antiviral treatment regimen
with peginterferon alfa and ribavirin in HCV genotype 1 infected
subjects with compensated liver disease.
[0057] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of postmenopausal women with advanced
hormone receptor-positive, HER2-negative breast cancer (advanced
HR+ BC), e.g., in combination with exemestane after failure of
treatment with letrozole or anastrozole. In one embodiment, the
CYP3A4 substrate drug can be indicated for the treatment of
patients with progressive neuroendocrine tumors of pancreatic
origin (PNET). In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of patients with progressive,
well-differentiated, non-functional neuroendocrine tumors (NET) of
gastrointestinal (GI) or lung origin that are unresectable, locally
advanced or metastatic. In one embodiment, the CYP3A4 substrate
drug can be indicated for the treatment of patients with advanced
renal cell carcinoma (RCC), e.g., after failure of treatment with
sunitinib or sorafenib. In one embodiment, the CYP3A4 substrate
drug can be indicated for the treatment of patients with renal
angiomyolipoma and tuberous sclerosis complex (TSC), not requiring
immediate surgery. In one embodiment, the CYP3A4 substrate drug can
be indicated for the treatment of patients with TSC who have
subependymal giant cell astrocytoma (SEGA) that require therapeutic
intervention but are not candidates for surgical resection.
[0058] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of type 2 diabetes mellitus, e.g., as
an adjunct to diet and exercise to improve glycemic control in
adults.
[0059] In one embodiment, the CYP3A4 substrate drug can be
indicated to reduce the rate of thrombotic cardiovascular events
(e.g., cardiovascular death, myocardial infarction, or stroke) in
patients with acute coronary syndrome (ACS).
[0060] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of major depressive disorder (MDD).
[0061] In one embodiment, the CYP3A4 substrate drug can be
indicated to reduce the risk of stroke and systemic embolism in
patients with nonvalvular atrial fibrillation. In one embodiment,
the CYP3A4 substrate drug can be indicated for the prophylaxis of
deep vein thrombosis (DVT), which may lead to pulmonary embolism
(PE), e.g., in patients who have undergone hip or knee replacement
surgery. In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of DVT or PE. In one embodiment, the
CYP3A4 substrate drug can be indicated to reduce the risk of
recurrent DVT and PE following initial therapy.
[0062] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of moderate to severe active rheumatoid
arthritis, e.g., in patients who have had inadequate response or
tolerance to methotrexate.
[0063] In one embodiment, the CYP3A4 substrate drug can be
indicated for the acute treatment of migraine with or without
aura.
[0064] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of chronic phase and accelerated phase
Philadelphia chromosome positive chronic myeloid leukemia (Ph+
CIVIL), e.g., in newly diagnosed patients or in patients resistant
to or intolerant to prior therapy that included imatinib.
[0065] In one embodiment, the CYP3A4 substrate drug can be
indicated to reduce the risk of hospitalization for atrial
fibrillation (AF), e.g., in patients with a history of paroxysmal
or persistent AF or atrial flutter (AFK), who are in sinus rhythm
or will be cardioverted.
[0066] In one embodiment, the CYP3A4 substrate drug can be
indicated for maintenance treatment of asthma, e.g., in patients
aged 4 years and older. In one embodiment, the CYP3A4 substrate
drug can be indicated for maintenance treatment of airflow
obstruction and reducing exacerbations in patients with chronic
obstructive pulmonary disease.
[0067] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of erectile dysfunction (ED). In one
embodiment, the CYP3A4 substrate drug can be indicated for the
treatment of benign prostatic hyperplasia (BPH). In one embodiment,
the CYP3A4 substrate drug can be indicated for treatment of
pulmonary arterial hypertension (PAH) (WHO Group 1) to improve
exercise ability.
[0068] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of gout flares. In one embodiment, the
CYP3A4 substrate drug can be indicated for the treatment of
Familial Mediterranean fever.
[0069] In one embodiment, the CYP3A4 substrate drug can be
indicated for mantle cell lymphoma in patients who have received at
least one prior therapy. In one embodiment, the CYP3A4 substrate
drug can be indicated for chronic lymphocytic leukemia/small
lymphocytic lymphoma In one embodiment, the CYP3A4 substrate drug
can be indicated for chronic lymphocytic leukemia/small lymphocytic
lymphoma with 17p deletion.
[0070] In one embodiment, the CYP3A4 substrate drug can be
indicated for Waldenstrom's macroglobulinemia.
[0071] In one embodiment, the CYP3A4 substrate drug can be
indicated for marginal zone lymphoma who require systemic therapy
and have received at least one prior anti-CD20-based therapy.
[0072] In one embodiment, the CYP3A4 substrate drug can be
indicated for unresectable or metastatic melanoma with a BRAF V600E
or V600K mutation.
[0073] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of hormone-refractory metastatic
prostate cancer previously treated with a docetaxel-containing
treatment regimen.
[0074] In one embodiment, the CYP3A4 substrate drug can be
indicated for treatment of clinically significant hypervolemic and
euvolemic hyponatremia; including patients with heart failure and
Syndrome of Inappropriate Antidiuretic Hormone (SIADH).
[0075] In one embodiment, the CYP3A4 substrate drug can be
indicated for the prevention of acute and delayed nausea and
vomiting associated with initial and repeat courses of highly
emetogenic cancer chemotherapy (HEC) including high-dose
cisplatin.
[0076] In one embodiment, the CYP3A4 substrate drug can be
indicated for the prevention of delayed nausea and vomiting
associated with initial and repeat courses of moderately emetogenic
cancer chemotherapy (MEC).
[0077] In one embodiment, the CYP3A4 substrate drug can be
indicated for treatment of over-active bladder with symptoms of
urge urinary incontinence, urgency, and urinary frequency.
[0078] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of patients with metastatic non-small
cell lung cancer (NSCLC) whose tumors have epidermal growth factor
receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution
mutations as detected by an FDA-approved test receiving first-line,
maintenance, or second or greater line treatment after
progression.
[0079] In one embodiment, the CYP3A4 substrate drug can be
indicated for the first-line treatment of patients with locally
advanced, unresectable or metastatic pancreatic cancer, in
combination with gemcitabine.
[0080] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of patients with HER2-positive,
metastatic breast cancer who previously received trastuzumab and a
taxane, separately or in combination in patients who have either:
received prior therapy for metastatic disease or developed disease
recurrence during or within six months of completing adjuvant
therapy.
[0081] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of adult patients with chronic,
accelerated, or blast phase Ph+ chronic myelogenous leukemia (CML)
with resistance or intolerance to prior therapy.
[0082] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of gastrointestinal stromal tumor
(GIST) after disease progression on or intolerance to imatinib
mesylate.
[0083] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of advanced renal cell carcinoma (RCC);
progressive, well-differentiated pancreatic neuroendocrine tumors
(pNET) in patients with unresectable locally advanced or metastatic
disease.
[0084] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of only CCR5-tropic HIV-1 infection in
patients 2 years of age and older weighing at least 10 kg in
combination with other antiretroviral agents.
[0085] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of patients with advanced renal cell
carcinoma.
[0086] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of patients with advanced soft tissue
sarcoma who have received prior chemotherapy.
[0087] In one embodiment, the CYP3A4 substrate drug can be
indicated for the acute treatment of manic and mixed episodes
associated with Bipolar I.
[0088] In one embodiment, the CYP3A4 substrate drug can be
indicated for the adjunctive treatment of Major Depressive
Disorder.
[0089] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of irritability associated with
Autistic Disorder.
[0090] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of Tourette's disorder.
[0091] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of agitation associated with
schizophrenia or bipolar mania.
[0092] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of advanced renal cell carcinoma after
failure of one prior systemic therapy.
[0093] In one embodiment, the CYP3A4 substrate drug can be
indicated to improve glycemic control in adults with type 2
diabetes mellitus (T2DM) who have inadequate control with
dapagliflozin or who are already treated with dapagliflozin and
saxagliptin.
[0094] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of patients with progressive,
metastatic medullary thyroid cancer (MTC).
[0095] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of patients with advanced renal cell
carcinoma (RCC) who have received prior anti-angiogenic
therapy.
[0096] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of adult patients with chronic phase,
accelerated phase, or blast phase chronic myeloid leukemia (CIVIL)
or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI)
therapy is indicated.
[0097] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of adult patients with T315I-positive
CML (chronic phase, accelerated phase, or blast phase) or
T315I-positive Philadelphia chromosome positive acute lymphoblastic
leukemia (Ph+ ALL).
[0098] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of invasive aspergillosis.
[0099] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of invasive mucormycosis; to reduce
low-density lipoprotein cholesterol (LDL-C), total cholesterol
(TC), apolipoprotein B (apo B), and non-high density lipoprotein
cholesterol (non-HDL-C) in patients with homozygous familial
hypercholesterolemia (HoFH).
[0100] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of schizophrenia in adults.
[0101] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of hormone receptor (HR)-positive;
human epidermal growth factor receptor 2 (HER2)-negative advanced
or metastatic breast cancer in combination with an aromatase
inhibitor as initial endocrine based therapy in postmenopausal
women, or fulvestrant in women with disease progression following
endocrine therapy.
[0102] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of Major Depressive Disorder (MDD).
[0103] In one embodiment, the CYP3A4 substrate drug can be
indicated for the suppression of motor and phonic tics in patients
with Tourette's Disorder who have failed to respond satisfactorily
to standard treatment.
[0104] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of multiple myeloma in patients who
have received at least two prior therapies including lenalidomide
and a proteasome inhibitor and have demonstrated disease
progression on or within 60 days of completion of the last
therapy.
[0105] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of non-small cell lung cancer (NSCLC)
whose disease has not progressed after four cycles of
platinum-based first-line chemotherapy.
[0106] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of locally advanced or metastatic NSCLC
after failure of at least one prior chemotherapy regimen.
[0107] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of locally advanced, unresectable or
metastatic pancreatic cancer.
[0108] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of overactive bladder with symptoms of
urge urinary incontinence, urgency, and urinary frequency.
[0109] In one embodiment, the CYP3A4 substrate can be indicated for
the treatment of advanced renal cell carcinoma (RCC) after failure
of treatment with sunitinib or sorafenib.
[0110] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of subependymal giant cell astrocytoma
(SEGA) associated with tuberous sclerosis complex (TSC) who require
therapeutic intervention but are not candidates for curative
surgical resection.
[0111] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of renal angiomyolipoma and tuberous
sclerosis complex.
[0112] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of hormone receptor (HR)-positive,
human epidermal growth factor receptor 2 (HER2)-negative advanced
or metastatic breast cancer with disease progression following
endocrine therapy in women in combination with fulvestrant.
[0113] In one embodiment, the CYP3A4 substrate drug can be used as
monotherapy for the treatment of adult patients with HRpositive,
HER2-negative advanced or metastatic breast cancer with disease
progression following endocrine therapy and prior chemotherapy in
the metastatic setting.
[0114] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of cystic fibrosis (CF) in patients age
2 years and older who have one mutation in the CFTR gene that is
responsive to ivacaftor based on clinical and/or in vitro assay
data.
[0115] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of deleterious or suspected deleterious
germline BRCA-mutated advanced ovarian cancer in adult patients who
have been treated with three or more prior lines of
chemotherapy.
[0116] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of intermediate or high-risk
myelofibrosis, including primary myelofibrosis, post-polycythemia
vera myelofibrosis and post-essential thrombocythemia
myelofibrosis.
[0117] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of polycythemia vera patients who have
had an inadequate response to or are intolerant of hydroxyurea.
[0118] In one embodiment, the CYP3A4 substrate drug can be
indicated as an adjunctive therapy to antidepressants for the
treatment of major depressive disorder (MDD).
[0119] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of schizophrenia.
[0120] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of cystic fibrosis (CF) patients aged
12 years and older who are homozygous for the F508del mutation or
who have at least one mutation in the cystic fibrosis transmembrane
conductance regulator (CFTR) gene that is responsive to
tezacaftor/ivacaftor based on in vitro data and/or clinical
evidence.
[0121] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of metastatic colorectal cancer (CRC)
patients who have been previously treated with fluoropyrimidine-,
oxaliplatin- and irinotecan-based chemotherapy, an antiVEGF
therapy, and, if RAS wild-type, an anti-EGFR therapy.
[0122] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of locally advanced, unresectable or
metastatic gastrointestinal stromal tumor (GIST) patients who have
been previously treated with imatinib mesylate and sunitinib
malate.
[0123] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of hepatocellular carcinoma (HCC) in
patients who have been previously treated with sorafenib.
[0124] In one embodiment, the CYP3A4 substrate drug can be
indicated for the use with sofosbuvir, with or without ribavirin,
for the treatment of chronic HCV genotype 1 or 3 infection.
[0125] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of metastatic non-small cell lung
cancer (NSCLC) patients whose tumors are anaplastic lymphoma kinase
(ALK) or ROS1-positive as detected by an FDA-approved test.
[0126] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of opioid induced constipation (OIC) in
adult patients with chronic non-cancer pain, including patients
with chronic pain related to prior cancer or its treatment who do
not require frequent (e.g., weekly) opioid dosage escalation.
[0127] In one embodiment, the CYP3A4 substrate drug can be
indicated for the treatment of unresectable or metastatic melanoma
with BRAF V600E mutation as detected by an FDA-approved test.
[0128] In one embodiment, the CYP3A4 substrate drug can be
indicated in combination with trametinib, for the treatment of
patients with unresectable or metastatic melanoma with BRAF V600E
or V600K mutations as detected by an FDA-approved test.
[0129] In one embodiment, the CYP3A4 substrate drug can be
indicated in combination with trametinib, for the treatment of
patients with melanoma with BRAF V600E or V600K mutations, as
detected by an FDA-approved test, and involvement of lymph node(s),
following complete resection.
[0130] In one embodiment, the CYP3A4 substrate drug can be
indicated in combination with trametinib, for the treatment of
metastatic non-small cell lung cancer (NSCLC) with BRAF V600E
mutation as detected by an FDA-approved test.
[0131] In one embodiment, the CYP3A4 substrate drug can be
indicated in combination with trametinib, for the treatment of
locally advanced or metastatic anaplastic thyroid cancer (ATC) with
BRAF V600E mutation and with no satisfactory locoregional treatment
options.
[0132] In one embodiment, the CYP3A4 substrate drug can be
indicated with or without ribavirin for treatment of chronic HCV
genotypes 1 or 4 infection in adults.
[0133] Other non-limiting examples of conditions or diseases for
which CYP3A4 substrate drugs are prescribed include antiretroviral
therapy, e.g., for the treatment of HIV/AIDS, anxiety disorders,
panic disorders, seizures, insomnia, hypertension, cardiovascular
disease (e.g., myocardial infarction, stroke, and angina),
hyperlipidemia, cancer, such as primary kidney cancer, advanced
primary liver cancer, radioactive iodine resistant advanced thyroid
carcinoma, renal cell carcinoma, imatinib-resistant
gastrointestinal stromal tumor, allergies, and transplantation.
[0134] As discussed above, after stopping treatment with a strong
CYP3A4 inhibitor (including but not limited to posaconazole),
posaconazole accumulates in the body of patients, and reduces or
prevents metabolism of CYP3A4 substrate drugs. Thus, patients
previously on posaconazole that are concomitantly treated with
CYP3A4 substrate drugs may have plasma levels of the CYP3A4
substrate drug that exceed the plasma levels of an otherwise
identical patient that was not previously treated with
posaconazole. Described herein, in various embodiments, are
treatment regimens for CYP3A4 substrate drugs which are applicable
to patients who previously received multiple doses of a strong
CYP3A4 inhibitor (e.g., posaconazole) for a period of about 2-21
days after stopping treatment with the strong CYP3A4 inhibitor. In
some embodiments, the treatment regimen provides for treating or
prescribing a dose which is less than about 50% of the reference
dose of the CYP3A4 substrate drug for a period of about 2-21 days
after stopping posaconazole treatment. As used herein, a dose that
is less than 50% of the reference dose of the CYP3A4 inhibitor can
include any amount from 0% (i.e., no dose) to about 50% of the
CYP3A4 inhibitor for the period of 2-21 days. Therefore, the
treatment regimen disclosed herein can include, in some
embodiments, delaying a first dose of a CYP3A4 substrate drug for
about 2-21 days after stopping posaconazole treatment, or
alternatively, treating with a reduced dose of the CYP3A4 substrate
drug for about 2-21 days after stopping posaconazole treatment. The
methods described herein can be applied to any patient that was
previously on posaconazole and having an indication amenable to
treatment with a CYP3A4 substrate drug, including normal patients
(non-obese and normal metabolizers), obese patients, and poor or
intermediate metabolizers, or combinations thereof.
[0135] In some embodiments, between about 2 and about 42 days,
e.g., about 2, about 3, about 4, about 5, about 6, about 7, about
8, about 9, about 10, about 11, about 12 days, about 13, about 14,
about 15, about 16, about 17, about 18, about 19, about 20, about
21 days, about 22 days, about 23, about 24, about 25, about 26,
about 27, about 28, about 29, about 30, about 31 days, about 32
days, about 33, about 34, about 35, about 36, about 37, about 38,
about 39, about 40, about 41 days, or about 42 days inclusive of
all ranges and subranges therebetween, should elapse between
discontinuation of posaconazole (i.e., the last dose in a
posaconazole regimen) and initiation of treatment with a CYP3A4
substrate drug (i.e., the first dose in a CYP3A4 regimen of any of
the CYP3A4 substrate drugs described herein). In some embodiments,
the patient is a "normal" patient (i.e., a patient with "normal"
CYP3A4 enzyme function, often termed an "extensive metabolizer" in
the art; and having a normal weight--e.g., a BMI in the range of
about 18.5-24.9), and in other embodiments the patient has one of
the physiological characteristics described herein, e.g., is
considered obese and/or has a level of CYP3A4 enzyme activity
termed in the art as poor or intermediate.
[0136] This "delay" or waiting period between ceasing or stopping
the treatment of posaconazole and initiating treatment with a
CYP3A4 substrate drug can equivalently be characterized as the time
that elapses between stopping treatment of posaconazole and
treating with the first dose of CYP3A4 substrate drug. The skilled
artisan will recognize that additional doses of the CYP3A4
substrate drug are typically administered or prescribed
subsequently, but the "delay" or "washout" period as described
herein is the time that elapses between stopping treatment of
posaconazole and the first dose that initiates treatment with a
CYP3A4 substrate drug.
[0137] In alternative embodiments, rather than delaying the
treatment of the CYP3A4 substrate drug, after stopping treatment of
posaconazole the CYP3A4 substrate drug is treated or prescribed at
a dose which is no more than about 50% of a reference dose (the
dose recommended for the patient on the FDA-approved label for the
CYP3A4 substrate drug), including e.g., no more than about 50%, no
more than about 49%, no more than about 48%, no more than about
47%, no more than about 46%, no more than about 45%, no more than
about 44%, no more than about 43%, no more than about 42%, no more
than about 41%, no more than about 40%, no more than about 39%, no
more than about 38%, no more than about 37%, no more than about
36%, no more than about 35%, no more than about 34%, no more than
about 33%, no more than about 32%, no more than about 31%, no more
than about 30%, no more than about 29%, no more than about 28%, no
more than about 27%, no more than about 26%, no more than about
25%, no more than about 24%, no more than about 23%, no more than
about 22%, no more than about 21%, no more than about 20%, no more
than about 19%, no more than about 18%, no more than about 17%, no
more than about 16%, no more than about 15%, no more than about
14%, no more than about 13%, no more than about 12%, no more than
about 11%, or no more than about 10% of the reference dose,
inclusive of all ranges and subranges therebetween, for at least
about 2-21 days after discontinuation of the posaconazole regimen,
e.g., for about 2, about 3, about 4, about 5, about 6, about 7,
about 8, about 9, about 10, about 11, about 12 days, about 13,
about 14, about 15, about 16, about 17, about 18, about 19, about
20, about 21 days, about 22 days, about 23, about 24, about 25,
about 26, about 27, about 28, about 29, about 30, about 31 days,
about 32 days, about 33, about 34, about 35, about 36, about 37,
about 38, about 39, about 40, about 41 days, or about 42 days,
inclusive of all ranges and subranges therebetween.
[0138] In other alternative embodiments, depending on the CYP3A4
substrate drug, the patient can be treated with or prescribed a
CYP3A4 substrate drug at a dose which is less than 100% of a
reference dose (the dose recommended for the patient on the
FDA-approved label for the CYP3A4 substrate drug), including e.g.,
about 95%, about 90%, about 85%, about 80%, about 75%, about 70%,
about 65%, about 60%, about 55%, or about 50% of the reference
dose, inclusive of all ranges and subranges therebetween, for at
least about 2-42 days after discontinuation of the posaconazole
treatment, e.g., for about 2, about 3, about 4, about 5, about 6,
about 7, about 8, about 9, about 10, about 11, about 12 days, about
13, about 14, about 15, about 16, about 17, about 18, about 19,
about 20, about 21 days, about 22 days, about 23, about 24, about
25, about 26, about 27, about 28, about 29, about 30, about 31
days, about 32 days, about 33, about 34, about 35, about 36, about
37, about 38, about 39, about 40, about 41 days, or about 42 days
inclusive of all ranges and subranges therebetween.
[0139] In addition to providing methods of treating or prescribing
treatment for "normal" patients (e.g., non-obese and normal CYP3A4
metabolizers), the present disclosure also provides methods for
treating, or prescribing treatment for, patients with at least one
of the physiological characteristics described herein, who had been
treated with multiple doses of posaconazole, with a CYP3A4
substrate drug. The treatment with the CYP3A4 substrate drug is
initiated or prescribed to be initiated (or the first dosing begins
after stopping treatment with posaconazole) after a delay time as
described herein, or is treated or prescribed at a reduced dose
(e.g., any amount less than 100% of a reference dose, including but
not limited to about 1/3, about 1/2, about 2/3, etc. of a reference
dose) for a time period after treatment with posaconazole is
stopped as described herein. The physiological characteristics of
such patients include reduced hepatic enzyme function, specifically
reduced CYP3A4 enzyme function (such patients are characterized in
the art as intermediate or poor CYP3A4 metabolizers), and/or a
weight or body fat status variously characterized as described
herein. In some embodiments, the patients can have various
characteristics of body fat status. The term "body fat status,"
"body fat characteristics," "obese status," "obese
characteristics," or other derivations or variations thereof refer
to at least seven characteristics (BMI, % IBW, waist size, % body
fat, % android fat, % gynoid fat, and total body fat) as described
herein. In some embodiments, the body fat status may be referred to
as obesity, and the patients may be referred to as obese, or obese
patients.
[0140] As described herein, the present Applicants have found that
certain classes of patients, i.e., patients having the particular
physiological characteristics described herein such as body fat and
weight status and/or hepatic metabolizing enzyme status, after
stopping treatment with posaconazole, may have substantially higher
plasma levels of posaconazole, and/or exhibit substantially longer
elimination half-lives (t.sub.1/2) of posaconazole than previously
known or contemplated, e.g., in the NOXAFIL.RTM. label, and
therefore require either a delay as described herein after stopping
posaconazole treatment, before treating, or prescribing a first
treatment to begin, with a CYP3A4 substrate drug, or a dose
adjustment (reduction) of the CYP3A4 substrate drug for a time
period after stopping posaconazole treatment, as described herein.
In some embodiments, the duration of the delay period or dose
adjustment period, or the degree of dose adjustment is greater than
the corresponding delay or dose reduction period/amount compared to
those considered to be "normal" patients. These classes of patients
which exhibit substantially higher plasma levels of posaconazole,
and/or exhibit substantially longer elimination half-lives
(t.sub.1/2) of posaconazole compared to the expected level (e.g.,
as embodied in the recommendations of the NOXAFIL.RTM. label), or
who require a longer delay time, dose adjustment time, or dose
adjustment level include obese patients who exhibit one or more of
e.g., a BMI of at least about 35, % IBW of at least about 150%,
waist size greater than about 42 inches, % body fat greater than
about 40%, % android body fat greater than about 40%, % gynoid body
fat greater than about 40%, total body fat greater than about 40
kg, optionally in combination with impaired hepatic function, e.g.,
intermediate or poor CYP3A4 metabolizers. Alternatively, patients
who are not obese (e.g., have any of the various measures of body
fat status described herein which are not considered as indicative
of obesity, such as a BMI less than about 35, % IBW of less than
about 150%, waist size less than about 42 inches, % body fat less
than about 40%, % android body fat less than about 40%, % gynoid
body fat less than about 40%, or total body fat less than about 40
kg) but have impaired hepatic metabolic function, e.g., are
considered intermediate or poor CYP3A4 metabolizers, have also been
found by the present Applicants to have substantially higher steady
state plasma levels of posaconazole, and/or exhibit a substantially
longer elimination half-lives (t.sub.1/2) of posaconazole compared
to those expected in "normal" patients--i.e., patients who do not
exhibit the specific physiological characteristics described
herein--or as embodied in the recommendations of the NOXAFIL.RTM.
label may also require an extended washout period (as described
herein) after stopping administration of posaconazole before
beginning treatment with a CYP3A4 substrate drug. Alternatively,
such patients may require an extended period (as described herein)
after stopping administration of posaconazole before beginning
treatment with a reduced dose (as described herein) relative to the
reference dose of the CYP3A4 substrate drug in order to minimize or
avoid adverse effects such as QTc prolongation or other side
effects of the CYP3A4 substrate drug than has hitherto been
recognized in the art. Conventionally, no such distinction between
patients having such physiological characteristics has been
recognized as requiring increased "washout" periods between dosing
with posaconazole and a CYP3A4 substrate drug, or as requiring time
periods during which a patient is treated, or prescribed to be
treated, with a reduced reference dose of the CYP3A4 substrate drug
after stopping administration of posaconazole, as the effects of
such physiological characteristics on steady state plasma levels of
posaconazole and/or elimination half-life was not previously
known.
[0141] Posaconazole can be metabolized primarily through oxidation
via Cytochrome P450 isozymes, in particular CYP3A4. Studies
indicate that other CYP isozymes, such as A2, 2C8, 2C9, 2D6 and
2E1, are not involved in the metabolism of posaconazole. Each
individual may have different activity levels of the P450 isozymes
that metabolize posaconazole. Categorizations of metabolizers may
include, but are not limited to, allelic heterogeneity in the P540
isozymes gene. For instance, the CYP3A4 gene can have allelic
heterogeneity and expression of CYP3A4*22 allele can be used to
classify individuals as reduced-expressers of CYP3A4 (i.e.,
individuals possessing one CYP3A4*22 allele), and normal-expressers
of CYP3A4 (i.e., individuals not possessing any CYP3A4*22
allele).
[0142] In some embodiments, the class of patients treated by the
methods of the present disclosure have a body mass index (BMI;
expressed in units of kg/m.sup.2 unless otherwise specified) of
less than about 25, e.g., about 24.5, about 24, about 23.5, about
23, about 22.5, about 22, about 21.5, about 21, about 20.5, about
20, about 19.5, about 19, or about 18.5 or less, inclusive of all
values and ranges therebetween.
[0143] In some embodiments, the class of patients treated by the
methods of the present disclosure have a body mass index (BMI;
expressed in units of kg/m.sup.2 unless otherwise specified) of at
least about 25, at least about 26, at least about 27, at least
about 28, at least about 29, at least about 30, at least about 31,
at least about 32, at least about 33, at least about 34, at least
about 35, at least about 36, at least about 37, at least about 38,
at least about 39, at least about 40, at least about 41, at least
about 42, at least about 43, at least about 44, at least about 45,
at least about 46, at least about 47, at least about 48, at least
about 49, at least about 50, at least about 51, at least about 52,
at least about 53, at least about 54, at least about 55, at least
about 56, at least about 57, at least about 58, at least about 59,
at least about 60, at least about 61, at least about 62, at least
about 63, at least about 64, at least about 65, at least about 66,
at least about 67, at least about 68, at least about 69, at least
about 70, at least about 71, at least about 72, at least about 73,
at least about 74, at least about 75, at least about 76, at least
about 77, at least about 78, at least about 79, at least about 80,
at least about 81, at least about 82, at least about 83, at least
about 84, at least about 85, at least about 86, at least about 87,
at least about 88, at least about 89, at least about 90, at least
about 91, at least about 92, at least about 93, at least about 94,
at least about 95, at least about 96, at least about 97, at least
about 98, at least about 99, at least about 100, at least about
101, at least about 102, at least about 103, at least about 104, at
least about 105, at least about 106, at least about 107, at least
about 108, at least about 109, at least about 110, at least about
111, at least about 112, at least about 113, at least about 114, at
least about 115, at least about 116, at least about 117, at least
about 118, at least about 119, at least about 120, at least about
121, at least about 122, at least about 123, at least about 124, at
least about 125, at least about 126, at least about 127, at least
about 128, at least about 129, at least about 130, at least about
131, at least about 132, at least about 133, at least about 134, at
least about 135, at least about 136, at least about 137, at least
about 138, at least about 139, at least about 140, at least about
141, at least about 142, at least about 143, at least about 144, at
least about 145, at least about 146, at least about 147, at least
about 148, at least about 149, at least about 150, at least about
151, at least about 152, at least about 153, at least about 154, at
least about 155, at least about 156, at least about 157, at least
about 158, at least about 159, at least about 160, at least about
161, at least about 162, at least about 163, at least about 164, at
least about 165, at least about 166, at least about 167, at least
about 168, at least about 169, at least about 170, at least about
171, at least about 172, at least about 173, at least about 174, at
least about 175, at least about 176, at least about 177, at least
about 178, at least about 179, at least about 180, at least about
181, at least about 182, at least about 183, at least about 184, at
least about 185, at least about 186, at least about 187, at least
about 188, at least about 189, at least about 190, at least about
191, at least about 192, at least about 193, at least about 194, at
least about 195, at least about 195, at least about 196, at least
about 197, at least about 198, at least about 199, at least about
200, at least about 201, at least about 202, at least about 203, at
least about 204, at least about 205, at least about 206, at least
about 207, at least about 208, at least about 209, or at least
about 210, inclusive of all ranges and subranges therebetween, and
any BMI described herein. In one embodiment, the patient has a body
mass index (BMI) of at least about 35. In another embodiment, the
patient has a body mass index (BMI) of at least about 40. In
another embodiment, the patient has a body mass index (BMI) of at
least 50.
[0144] In some embodiments, a patient treated according to the
methods of the present invention has a BMI of at least about 25 to
at least about 29.9, at least about 25.5 to at least about 29, at
least about 26 to at least about 28.5, at least about 26.5 to at
least about 28, or at least about 27 to at least about 27.5,
inclusive of all ranges and subranges therebetween, and can be
termed overweight or pre-obese. In some embodiments, a patient with
a BMI of at least about 30 to at least about 34.9, at least about
30.5 to at least about 34, at least about 31 to at least about
33.5, at least about 31.5 to at least about 33, or at least about
32 to at least about 32.5, inclusive of all ranges and subranges
therebetween can be considered obese. In some embodiments, a
patient with a BMI of at least about 35 to at least about 39.9, at
least about 35.5 to at least about 39, at least about 36 to at
least about 38.5, at least about 36.5 to at least about 38, or at
least about 37 to at least about 37.5, inclusive of all ranges and
subranges therebetween, and any BMI described herein, can be
considered obese. In other embodiments, a patient treated by the
methods of the present disclosure has a BMI of at least about 35 or
more, 40 or more, 50 or more, 60 or more, 70 or more, 80 or more,
90 or more, 100 or more, 110 or more, 120 or more, 130 or more, 140
or more, 150 or more, 160 or more, 170 or more, 180 or more, 190 or
more, 200 or more, or 210 or more, inclusive of all ranges and
subranges therebetween.
[0145] In some embodiments, the patient treated according to the
methods of the present disclosure is a child or an adolescent with
a BMI of at least about the 85.sup.th percentile to at least about
95.sup.th percentile, at least about the 86.sup.th percentile to at
least about 94.sup.th percentile, at least about the 87.sup.th
percentile to at least about 93.sup.th percentile, at least about
the 88.sup.th percentile to at least about 92.sup.th percentile, at
least about the 89.sup.th percentile to at least about 90.sup.th
percentile, inclusive of all ranges and subranges therebetween, can
be considered overweight or pre-obese. In some embodiments, the
patient is a patient with a BMI of at least about the 95.sup.th
percentile, at least about 96.sup.th percentile, at least about the
97.sup.th percentile, at least about 98.sup.th percentile, at least
about 99.sup.th percentile, or at least about 100.sup.th
percentile, inclusive of all ranges and subranges therebetween, and
any BMI percentile described herein, and can be considered obese.
In one embodiment, the patient is about 5 to about 19 years old or
about 7 to about 18 years old.
[0146] In some embodiments, the patient treated according to the
methods of the present disclosure is a female patient in the first
trimester through third trimester of a pregnancy and has a BMI of
at least 25 to at least about 29.9, at least about 25.5 to at least
about 29, at least about 26 to at least about 28.5, at least about
26.5 to at least about 28, or at least about 27 to at least about
27.5, inclusive of all ranges and subranges therebetween, and can
be considered overweight or pre-obese. In some embodiments, the
patient is a female patient in the first trimester through third
trimester of a pregnancy and has a BMI of at least about 30 to at
least about 34.9, at least about 30.5 to at least about 34, at
least about 31 to at least about 33.5, at least about 31.5 to at
least about 33, or at least about 32 to at least about 32.5,
inclusive of all ranges and subranges therebetween, and can be
considered obese. In some embodiments, the patent treated according
to the methods of the present invention is a female patient in the
first trimester through third trimester of a pregnancy and has a
BMI of at least about 35 to at least about 39.9, at least about
35.5 to at least about 39, at least about 36 to at least about
38.5, at least about 36.5 to at least about 38, at least about 37
to at least about 37.5, inclusive of all ranges and subranges
therebetween, and can be considered severely obese.
[0147] In some embodiments, methods of calculating BMI may include,
but are not limited to body weight in kilogram/(height in meters),
body weight in pounds/(height in inches)].times.703, and the
like.
[0148] In some embodiments, the patient treated according to the
methods of the present disclosure can alternatively be described as
having a % ideal body weight (% IBW) of at least about 110%, at
least about 111%, at least about 112%, at least about 113%, at
least about 114%, at least about 115%, at least about 116%, at
least about 117%, at least about 118%, at least about 119%, at
least about 120%, at least about 121%, at least about 122%, at
least about 123%, at least about 124%, at least about 125%, at
least about 126%, at least about 127%, at least about 128%, at
least about 129%, at least about 130%, at least about 131%, at
least about 132%, at least about 133%, at least about 134%, at
least about 135%, at least about 136%, at least about 137%, at
least about 138%, at least about 139%, at least about 140%, at
least about 141%, at least about 142%, at least about 143%, at
least about 144%, at least about 145%, at least about 146%, at
least about 147%, at least about 148%, at least about 149%, at
least about 150%, at least about 151%, at least about 152%, at
least about 153%, at least about 154%, at least about 155%, at
least about 156%, at least about 157%, at least about 158%, at
least about 159%, at least about 160%, at least about 161%, at
least about 162%, at least about 163%, at least about 164%, at
least about 165%, at least about 166%, at least about 167%, at
least about 168%, at least about 169%, at least about 170%, at
least about 171%, at least about 172%, at least about 173%, at
least about 174%, at least about 175%, at least about 176%, at
least about 177%, at least about 178%, at least about 179%, at
least about 180%, at least about 181%, at least about 182%, at
least about 183%, at least about 184%, at least about 185%, at
least about 186%, at least about 187%, at least about 188%, at
least about 189%, at least about 190%, at least about 191%, at
least about 192%, at least about 193%, at least about 194%, at
least about 195%, at least about 196%, at least about 197%, at
least about 198%, at least about 199%, at least about 200%, at
least about 201%, at least about 202%, at least about 203%, at
least about 204%, at least about 205%, at least about 206%, at
least about 207%, at least about 208%, at least about 209%, at
least about 210%, at least about 211%, at least about 212%, at
least about 213%, at least about 214%, at least about 215%, at
least about 216%, at least about 217%, at least about 218%, at
least about 219%, at least about 220%, at least about 221%, at
least about 222%, at least about 223%, at least about 224%, at
least about 225%, at least about 226%, at least about 227%, at
least about 228%, at least about 229%, at least about 230%, at
least about 231%, at least about 232%, at least about 233%, at
least about 234%, at least about 235%, at least about 236%, at
least about 237%, at least about 238%, at least about 239%, at
least about 240%, at least about 241%, at least about 242%, at
least about 243%, at least about 244%, at least about 245%, at
least about 246%, at least about 247%, at least about 248%, at
least about 249%, at least about 250%, at least about 251%, at
least about 252%, at least about 253%, at least about 254%, at
least about 255%, at least about 256%, at least about 257%, at
least about 258%, at least about 259%, at least about 260%, at
least about 261%, at least about 262%, at least about 263%, at
least about 264%, at least about 265%, at least about 266%, at
least about 267%, at least about 268%, at least about 269%, at
least about 270%, at least about 271%, at least about 272%, at
least about 273%, at least about 274%, at least about 275%, at
least about 276%, at least about 277%, at least about 278%, at
least about 279%, or at least about 280%, inclusive of all ranges
and subranges therebetween, and any % ideal body weight described
herein. In one embodiment, the patient has % ideal body weight
(IBW) of at least about 150%. In one embodiment, the patient has %
ideal body weight (IBW) of at least about 250%. In other
embodiments, the patient has % IBW of at least 150% and can be
considered obese.
[0149] In some embodiments, the patient treated according to the
present disclosure can alternatively be described as having a waist
size or waist circumference greater than about 32, greater than
about 33, greater than about 34, greater than about 35 inches,
greater than about 36, greater than about 37, greater than about
38, greater than about 39, greater than about 40, greater than
about 41, greater than about 42, greater than about 43, greater
than about 44, greater than about 45, greater than about 46,
greater than about 47, greater than about 48, greater than about
49, greater than about 50, greater than about 51, greater than
about 52, greater than about 53, greater than about 54, greater
than about 55, greater than about 56, greater than about 57,
greater than about 58, greater than about 59, greater than about 60
inches, greater than about 61 inches, greater than about 62 inches,
greater than about 63 inches, greater than about 64 inches, greater
than about 65 inches, inclusive of all ranges and subranges
therebetween, and any waist size or circumference described herein.
In one embodiment, a patient having a waist size or waist
circumference of about 42 inches can be considered obese. In
another embodiment, the patient has waist size or waist
circumference greater than about 48 inches. In other embodiment,
the patient has waist or waist circumference of at least 42
inches.
[0150] In some embodiments, the patient treated according to the
methods of the present disclosure can alternatively be described as
having a % body fat greater than about 20%, greater than about 21%,
greater than about 22%, greater than about 23%, greater than about
24%, greater than about 25%, greater than about 26%, greater than
about 27%, greater than about 28%, greater than about 29%, greater
than about 30%, greater than about 31%, greater than about 32%,
greater than about 33%, greater than about 34%, greater than about
35%, greater than about 36%, greater than about 37%, greater than
about 38%, greater than about 39%, greater than about 40%, greater
than about 41%, greater than about 42%, greater than about 43%,
greater than about 44%, greater than about 45%, greater than about
46%, greater than about 47%, greater than about 48%, greater than
about 49%, or greater than about 50%, inclusive of all ranges and
subranges therebetween, and any % body fat described herein. In one
embodiment, the patient has a % body fat greater than about 40%. In
one embodiment, the patient has a % body fat of at least about 50%.
In another embodiment, a patient having a % body fat greater than
about 40% can be considered obese. In some embodiments, methods of
calculating % body fat can include, but are not limited to total
body fat expressed as a percentage of total body weight. Other
standards for obesity can be used. For example, the American
Council on Exercise suggests that an "average" percentage of body
fat for women is about 25-31%, and for men, about 18-24%, and for
obese women, about 32% and higher, and obese men, about 25% and
higher.
[0151] In other embodiments, the patient can alternatively be
described as having a android body fat greater than about 30%,
greater than about 31%, greater than about 32%, greater than about
33%, greater than about 34%, greater than about 35%, greater than
about 36%, greater than about 37%, greater than about 38%, greater
than about 39%, greater than about 40%, greater than about 41%,
greater than about 42%, greater than about 43%, greater than about
44%, greater than about 45%, greater than about 46%, greater than
about 47%, greater than about 48%, greater than about 49%, greater
than about 50%, greater than about 51%, greater than about 52%,
greater than about 53%, greater than about 54%, greater than about
55%, greater than about 56%, greater than about 57%, greater than
about 58%, greater than about 59%, greater than about 60%, greater
than about 61%, greater than about 62%, greater than about 63%,
greater than about 64%, greater than about 65%, greater than about
66%, greater than about 67%, greater than about 68%, greater than
about 69%, greater than about 70%, greater than about 71%, greater
than about 72%, greater than about 73%, greater than about 74%,
greater than about 75%, greater than about 76%, greater than about
77%, greater than about 78%, greater than about 79%, or greater
than about 80%, inclusive of all ranges and subranges therebetween,
and any % android body fat described herein. In one embodiment, a
patient having a % android body fat greater than about 40% can be
considered obese. In one embodiment, a patient having a % android
body fat greater than about 50% can be considered obese
[0152] In other embodiments, the patient can alternatively be
described as having a % android body fat of at least about 30%, at
least about 31%, at least about 32%, at least about 33%, at least
about 34%, at least about 35%, at least about 36%, at least about
37%, at least about 38%, at least about 39%, at least about 40%, at
least about 41%, at least about 42%, at least about 43%, at least
about 44%, at least about 45%, at least about 46%, at least about
47%, at least about 48%, at least about 49%, at least about 50%, at
least about 51%, at least about 52%, at least about 53%, at least
about 54%, at least about 55%, at least about 56%, at least about
57%, at least about 58%, at least about 59%, at least about 60%, at
least about 61%, at least about 62%, at least about 63%, at least
about 64%, at least about 65%, at least about 66%, at least about
67%, at least about 68%, at least about 69%, at least about 70%, at
least about 71%, at least about 72%, at least about 73%, at least
about 74%, at least about 75%, at least about 76%, at least about
77%, at least about 78%, at least about 79%, or at least about 80%,
inclusive of all ranges and subranges therebetween, and % android
body fat described herein. In one embodiment, the patient has %
android body fat of at least about 50%.
[0153] In other embodiments, the patient can alternatively be
described as having a gynoid body fat greater than about 30%,
greater than about 31%, greater than about 32%, greater than about
33%, greater than about 34%, greater than about 35%, greater than
about 36%, greater than about 37%, greater than about 38%, greater
than about 39%, greater than about 40%, greater than about 41%,
greater than about 42%, greater than about 43%, greater than about
44%, greater than about 45%, greater than about 46%, greater than
about 47%, greater than about 48%, greater than about 49%, greater
than about 50%, greater than about 51%, greater than about 52%,
greater than about 53%, greater than about 54%, greater than about
55%, greater than about 56%, greater than about 57%, greater than
about 58%, greater than about 59%, greater than about 60%, greater
than about 61%, greater than about 62%, greater than about 63%,
greater than about 64%, greater than about 65%, greater than about
66%, greater than about 67%, greater than about 68%, greater than
about 69%, greater than about 70%, greater than about 71%, greater
than about 72%, greater than about 73%, greater than about 74%,
greater than about 75%, greater than about 76%, greater than about
77%, greater than about 78%, greater than about 79%, or greater
than about 80%, inclusive of all ranges and subranges therebetween,
and any % gynoid body fat described herein. In one embodiment, a
patient having a % gynoid body fat greater than about 40% can be
considered obese. In one embodiment, a patient having a % gynoid
body fat greater than about 50% can be considered obese.
[0154] In other embodiments, the patient can alternatively be
described as having a total body fat content greater than about 30
kg, greater than about 31 kg, greater than about 32 kg, greater
than about 33 kg, greater than about 34 kg, greater than about 35
kg, greater than about 36 kg, greater than about 37 kg, greater
than about 38 kg, greater than about 39 kg, greater than about 40
kg, greater than about 41 kg, greater than about 42 kg, greater
than about 43 kg, greater than about 44 kg, greater than about 45
kg, greater than about 46 kg, greater than about 47 kg, greater
than about 48 kg, greater than about 49 kg, greater than about 50
kg, greater than about 51 kg, greater than about 52 kg, greater
than about 53 kg, greater than about 54 kg, greater than about 55
kg, greater than about 56 kg, greater than about 57 kg, greater
than about 58 kg, greater than about 59 kg, greater than about 60
kg, greater than about 61 kg, greater than about 62 kg, greater
than about 63 kg, greater than about 64 kg, greater than about 65
kg, greater than about 66 kg, greater than about 67 kg, greater
than about 68 kg, greater than about 69 kg, greater than about 70
kg, greater than about 71 kg, greater than about 72 kg, greater
than about 73 kg, greater than about 74 kg, greater than about 75
kg, greater than about 76 kg, greater than about 77 kg, greater
than about 78 kg, greater than about 79 kg, greater than about 80
kg, greater than about 81 kg, greater than about 82 kg, greater
than about 83 kg, greater than about 84 kg, greater than about 85
kg, greater than about 86 kg, greater than about 87 kg, greater
than about 88 kg, greater than about 89 kg, greater than about 90
kg, greater than about 91 kg, greater than about 92 kg, greater
than about 93 kg, greater than about 94 kg, greater than about 95
kg, greater than about 96 kg, greater than about 97 kg, greater
than about 98 kg, greater than about 99 kg, greater than about 100
kg, at least 101 kg, at least 102 kg, at least 103 kg, at least 104
kg, at least 105 kg, at least 106 kg, at least 107 kg, at least 108
kg, at least 109 kg, or at least 110 kg, inclusive of all ranges
and subranges therebetween, and any total body fat described
herein. In one embodiment, a patient having total body fat greater
than about 40 kg can be considered obese. In one embodiment, a
patient having total body fat greater than about 50 kg can be
considered obese.
[0155] In other embodiments, the obesity status of patients treated
with the methods of the present disclosure can be measured by
waist-to-hip ratio. In other embodiments, the obesity status of
patients can be measured by skinfold thickness. In other
embodiments, the obesity status of patients can be measured by
bioelectric impedance. In other embodiments, the obesity status of
patients can be measured by underwater weighing or densitometry. In
other embodiments, the obesity status of patients can be measured
by air-displacement plethysmography. In other embodiments, the
obesity status of patients can be measured by dilution method or
hydrometry. In other embodiments, the obesity status of patients
can be measured by dual energy X-ray absorptiometry. In other
embodiments, the obesity status of patients can be measured by
computerized tomography and magnetic resonance imaging. In some
embodiments, the obesity status can be defined by, but is not
limited to adopting the clinical standards, conventional standards,
and/or the standards published by the World Health Organization and
Center of Disease Control (both of which are herein incorporated by
reference in their entireties for all purposes) when using the
methods described herein. For example, the WHO defines an obese
person as a person with a BMI of 30 or more, an overweight person
is one with a BMI equal to or more than 25 (to less than 30).
Similarly, the CDC defines normal as a BMI of 18.5 to less than 25,
25.0 to less than 30 as overweight, and 30.0 or higher as obese.
The CDC further subdivides obesity into 3 classes: Class 1, a BMI
of 30 to less than 35; Class 2, a BMI of 35 to less than 40; and
Class 3, as a BMI of 40 or higher. The CDC sometimes refers to
Class 3 obesity as "extreme" or "severe" obesity.
[0156] In some embodiments, the patient treated by the methods of
the present disclosure can be characterized by two or more of the
physiological characteristics described herein. For example the
patient can have a BMI of at least about 35 and can have a % IBW of
at least 150%. In some embodiments, the patient can have a BMI of
at least about 35 and can have a waist size greater than about 42
inches. In some embodiments, the patient can have a BMI of at least
about 35 and can have a % body fat greater than about 40%. In some
embodiments, the patient can have a BMI of at least about 35 and
can have a % android body fat greater than about 40%. In some
embodiments, the patient can have a BMI of at least about 35 and
can have a % gynoid body fat greater than about 40%. In some
embodiments, the patient can have a BMI of at least about 35 and
can have total body fat greater than about 40 kg. In various other
embodiments, the patient can have any combination of two or more of
any of the specific physiological parameters described herein.
[0157] In some embodiments, the patient can have three or more of
the physiological parameters described herein, for example a BMI of
at least about 35, a % IBW of at least 150%, and waist size greater
than about 42 inches. In some embodiments, the patient can have a
BMI of at least about 35, a % IBW of at least 150%, and a % body
fat greater than about 40%. In some embodiments, the patient can
have a BMI of at least about 35, a % IBW of at least 150%, and a %
android body fat greater than about 40%. In some embodiments, the
patient can have a BMI of at least about 35, a % IBW of at least
150%, and a % gynoid body fat greater than about 40%. In some
embodiments, the patient can have a BMI of at least about 35, a %
IBW of at least 150%, and total body fat greater than about 40 kg.
In various other embodiments, the patient can have any combination
of three or more of any of the specific physiological parameters
described herein.
[0158] In some embodiments, the patient can have four or more of
the physiological parameters described herein, for example the
patient can have a BMI of at least about 35, a % IBW of at least
150%, waist size greater than about 42 inches, and a % body fat
greater than about 40%. In some embodiments, the patient can have a
BMI of at least about 35, a % IBW of at least 150%, waist size
greater than about 42 inches, and a % android body fat greater than
about 40%. In some embodiments, the patient can have a BMI of at
least about 35, a % IBW of at least 150%, waist size greater than
about 42 inches, and a % gynoid body fat greater than about 40%. In
some embodiments, the patient can have a BMI of at least about 35,
a % IBW of at least 150%, a waist size greater than about 42
inches, and total body fat greater than about 43 kg. In some a
embodiments, the patient can have a BMI of at least about 35, a %
IBW of at least 150%, a waist size greater than about 42 inches, a
% body fat greater than about 40%, and a % android body fat greater
than about 40%. In some embodiments, the patient can have a BMI of
at least about 35, a % IBW of at least 150%, a waist size greater
than about 42 inches, a % body fat greater than about 40%, and a %
gynoid body fat greater than about 40%. In some embodiments, the
patient can have a BMI of at least about 35, a % IBW of at least
150%, a waist size greater than about 42 inches, a % body fat
greater than about 40%, and total body fat greater than about 40
kg. In some embodiments, the patient can have a BMI of at least
about 35, a % IBW of at least 150%, a waist size greater than about
42 inches, a % body fat greater than about 40%, a % android body
fat greater than about 40%, in % gynoid body fat greater than about
40%, and total body fat greater than about 40 kg. In one
embodiment, the patient who has a BMI of at least about 35, in %
IBW of at least 150%, a waist size greater than about 42 inches,
and a % body fat greater than about 40%, a % android body fat
greater than about 40%, a % gynoid body fat greater than about 40%,
and total body fat greater than about 40 kg. In various other
embodiments, the patient can have any combination of any or all of
the specific physiological parameters described herein.
[0159] In some embodiments, the patient can have a waist size
greater than about 42 inches, a % body fat greater than about 40%,
and a % android body fat greater than about 40%. In some
embodiments, the patient can have a waist size greater than about
42 inches, a % body fat greater than about 40%, and a % gynoid body
fat greater than about 40%. In some embodiments, the patient can
have a waist size greater than about 42 inches, a % body fat
greater than about 40%, and total body fat greater than about 40
kg.
[0160] In some embodiments, the patient can have a % body fat
greater than about 40%, a % android body fat greater than about
40%, and a % gynoid body fat greater than about 40%. In some
embodiments, the patient can have a % body fat greater than about
40%, a % android body fat greater than about 40%, and total body
fat greater than about 40 kg. In some embodiments, the patient can
have a % body fat greater than about 40%, a % gynoid body fat
greater than about 40%, and total body fat greater than about 40
kg. In some embodiments, a % android body fat greater than about
40%, and a % gynoid body fat greater than about 40%, and total body
fat greater than about 43 kg. In some embodiments, the patient can
have any combinations of obesity characteristics described
herein
[0161] In some embodiments, patients with at least one of the
obesity characteristics described herein can be an intermediate
CYP3A4 metabolizer. In other embodiments, the patients with at
least one of the obesity characteristics described herein can be a
poor CYP3A4 metabolizer. In some embodiments, the patients with at
least one of the obesity characteristics described herein can be an
extensive CYP3A4 metabolizer. In still other embodiments, the
patient is not obese, e.g., can have normal weight, and be an
intermediate or poor CYP3A4 metabolizer.
[0162] Alternatively, in some embodiments, the CYP3A4 genotype can
be tested by using targeted variant analysis. In some embodiments,
the CYP3A4 genotype can be tested by using sequence analysis of
select exons.
[0163] In various embodiments, the present disclosure also provides
for methods of treating patients previously treated with
posaconazole with a CYP3A4 substrate drug which is contraindicated
for concomitant use with a strong CYP3A4 inhibitor, such as
posaconazole, wherein the CYP3A4 substrate drug maintains an AUC
which is no more than about 2750% of a normal baseline AUC (as
defined above) of the CYP3A4 substrate drug, e.g., no more than
about 2700%, no more than about 2650%, no more than about 2600%, no
more than about 2550%, no more than about 2500%, no more than about
2450%, no more than about 2400%, no more than about 2350%, no more
than about 2300%, no more than about 2250%, no more than about
2200%, no more than about 2150%, no more than about 2100%, no more
than about 2050%, no more than about 2000%, no more than about
1950%, no more than about 1900%, no more than about 1850%, no more
than about 1800%, no more than about 1750%, no more than about
1700%, no more than about 1650%, no more than about 1600%, no more
than about 1550%, no more than about 1500%, no more than about
1450%, no more than about 1400%, no more than about 1350%, no more
than about 1300%, no more than about 1250%, no more than about
1200%, no more than about 1150%, no more than about 1100%, no more
than about 1050%, no more than about 1000%, no more than about
950%, no more than about 900%, no more than about 850%, no more
than about 800%, no more than about 750%, no more than about 700%,
no more than about 650%, no more than about 600%, no more than
about 550%, no more than about 500%, no more than about 450%, no
more than about 445%, no more than about 440%, no more than about
435%, no more than 430%, no more than about 425%, no more than
about 420%, no more than about 415%, no more than about 410%, no
more than about 405%, no more than about 400%, no more than about
395%, no more than about 390%, no more than about 385%, no more
than about 380%, no more than about 375%, no more than about 370%,
no more than about 365%, no more than about 360%, no more than
about 355%, no more than about 350%, no more than about 345%, no
more than about 340%, no more than about 335%, no more than 330%,
no more than about 325%, no more than about 320%, no more than
about 315%, no more than about 310%, no more than about 305%, or no
more than about 300%, no more than about 295%, no more than about
290%, no more than about 285%, no more than about 280%, no more
than about 275%, no more than about 270%, no more than about 265%,
no more than about 260%, no more than about 255%, no more than
about 250%, no more than about 245%, no more than about 240%, no
more than about 235%, no more than 230%, no more than about 225%,
no more than about 220%, no more than about 216%, no more than
about 215%, no more than about 210%, no more than about 205%, no
more than about 200%, no more than about 195%, no more than about
190%, no more than about 185%, no more than about 180%, no more
than about 175%, no more than about 170%, no more than about 165%,
no more than about 160%, no more than about 155%, no more than
about 150%, no more than about 145%, no more than about 140%, no
more than about 135%, no more than about 130%, no more than about
125%, no more than about 120%, no more than about 115%, no more
than about 110%, no more than about 105%, or no more than about
100% of the normal baseline AUC of the CYP3A4 substrate drug,
inclusive of all ranges and subranges therebetween. In particular
embodiments, the CYP3A4 substrate drug is ranolazine, and the AUC
of ranolazine is maintained at a level of no more than about 150%
of a normal baseline AUC of ranolazine. As used herein, the "normal
baseline AUC of ranolazine" refers to the steady state AUC.sub.0-12
measured for a particular dose of ranolazine in the absence of
other drugs. In some embodiments, the steady state AUC.sub.0-12 (%
CV) is 13,720 (67.0%) ng*h/mL measured after administration of 500
mg ranolazine. In some embodiments, the steady state AUC.sub.0-12
(% CV) is 32,091 (42.2%) ng*h/mL measured after administration of
1,000 mg ranolazine. In other particular embodiments, the CYP3A4
substrate drug is lurasidone, and the AUC of lurasidone is
maintained at a level of no more than about 216% of a normal
baseline AUC of lurasidone. As used herein, the "normal baseline
AUC of lurasidone" refers to the mean AUC.sub.0-tau measured for a
particular dose of lurasidone in the absence of other drugs. In
some embodiments, the mean AUC.sub.0-tau is about 743 ng*h/mL
measured after administration of 120 mg lurasidone administered in
the fed state after a 350 kcal meal. In other particular
embodiments, the CYP3A4 drug is tadalafil, and the AUC of tadalafil
is maintained at a level of no more than about 410% of a normal
baseline AUC of tadalafil. As used herein, the "normal baseline AUC
of tadalafil" refers to the mean AUC.sub.0-.infin. (% CV) measured
for a particular dose of tadalafil in the absence of other drugs.
In some embodiments, the mean AUC.sub.0-.infin. (% CV) is about
3647 (34.0%) .mu.g*h/L measured after administration of 10 mg
tadalafil. In some embodiments, the mean AUC.sub.0-.infin. (% CV)
is about 13,006 (43.9%) .mu.g*h/L for 20 mg tadalafil. In some
embodiments, the mean AUC.sub.0-.infin. (% CV) is within the range
of about 7,000 to about 13,000 (40.0%) .mu.g*h/L for 20 mg
tadalafil. In other particular embodiments, the CYP3A4 drug is
erlotinib, and the AUC of erlotinib is maintained at a level of no
more than about 164% of a normal baseline AUC of erlotinib at 150
mg. As used herein, the "normal baseline AUC of erlotinib" refers
to the mean AUC.sub.0-24 (% CV) measured for a particular dose of
erlotinib in the absence of other drugs. In some embodiments, the
mean AUC.sub.0-24 (% CV) at steady state is about 15.2 (400.0%)
.mu.g*h/mL measured after administration of 150 mg erlotinib. The
AUC.sub.0-24 of erlotinib is highly variable and tends to increase
in cancer patients relative to healthy volunteers. Thus, in some
embodiments, the mean AUC.sub.0-24 (% CV) can range from about 1
.mu.g*h/mL to about 35 .mu.g*h/mL, e.g., about 2 .mu.g*h/mL, about
3 .mu.g*h/mL, about 4 .mu.g*h/mL, about 5 .mu.g*h/mL, about 6
.mu.g*h/mL, about 7 .mu.g*h/mL, about 8 .mu.g*h/mL, about 9
.mu.g*h/mL, about 10 .mu.g*h/mL, about 11 .mu.g*h/mL, about 12
.mu.g*h/mL, about 13 .mu.g*h/mL, about 14 .mu.g*h/mL, about 15
.mu.g*h/mL, about 16 .mu.g*h/mL, about 17 .mu.g*h/mL, about 18
.mu.g*h/mL, about 19 .mu.g*h/mL, about 20 .mu.g*h/mL, about 21
.mu.g*h/mL, about 22 .mu.g*h/mL, about 23 .mu.g*h/mL, about 24
.mu.g*h/mL, about 25 .mu.g*h/mL, about 27 .mu.g*h/mL, about 28
.mu.g*h/mL, about 29 .mu.g*h/mL, about 30 .mu.g*h/mL, about 31
.mu.g*h/mL, about 32 .mu.g*h/mL, about 33 .mu.g*h/mL, about 34
.mu.g*h/mL, about 35 .mu.g*h/mL, about 36 .mu.g*h/mL, about 37
.mu.g*h/mL, about 38 .mu.g*h/mL, about 39 .mu.g*h/mL, about 40
.mu.g*h/mL, about 41 .mu.g*h/mL, about 42 .mu.g*h/mL, about 43
.mu.g*h/mL, about 44 .mu.g*h/mL, about 45 .mu.g*h/mL, about 47
.mu.g*h/mL, about 48 .mu.g*h/mL, about 49 .mu.g*h/mL, about 50
.mu.g*h/mL, about 51 .mu.g*h/mL, about 52 .mu.g*h/mL, about 53
.mu.g*h/mL, about 54 .mu.g*h/mL, about 55 .mu.g*h/mL, about 57
.mu.g*h/mL, about 58 .mu.g*h/mL, about 59 .mu.g*h/mL, about 60
.mu.g*h/mL, inclusive of all values and subranges therebetween. In
other particular embodiments, the CYP3A4 drug is solifenacin
succinate, and the AUC of solifenacin succinate is maintained at a
level of no more than about 270% of a normal baseline AUC of
solifenacin succinate. As used herein, the "normal baseline AUC of
solifenacin succinate" refers to the mean AUC.sub.0-24 (% CV) at
steady state measured for a particular dose of solifenacin
succinate in the absence of other drugs. In some embodiments, the
mean AUC.sub.0-24 (% CV) at steady state is about 463 (37%) ng*h/mL
for 5 mg solifenacin succinate. In some embodiments, the mean
AUC.sub.0-24 (% CV) at steady state is about 749 (22%) ng*h/mL for
10 mg solifenacin succinate. In other particular embodiments, the
CYP3A4 drug is everolimus, and the AUC of everolimus is maintained
at a level of no more than about 440% of a normal baseline AUC of
everolimus. As used herein, the "normal baseline AUC of everolimus"
refers to the mean AUC.sub.0-24.+-.SD measured at steady state
conditions for a particular dose of everolimus in the absence of
other drugs. In some embodiments, the mean AUC.sub.0-24.+-.SD is
about 536.+-.7.7 ng*h/mL measured after administration of 10 mg
everolimus.
[0164] In various other embodiments, the present disclosure
provides for methods of treating patients previously treated with
posaconazole, comprising treating or prescribing a reduced dose of
a CYP3A4 substrate drug which is contraindicated for concomitant
use with a strong CYP3A4 inhibitor (e.g., about 10%-90%, of the
reference dose) for a period of about 2-21 days after stopping
posaconazole treatment as described herein, wherein the CYP3A4
substrate drug is maintained an AUC which is no more than about
2750% of the baseline AUC of the CYP3A4 substrate drug, e.g., no
more than about 2700%, no more than about 2650%, no more than about
2600%, no more than about 2550%, no more than about 2500%, no more
than about 2450%, no more than about 2400%, no more than about
2350%, no more than about 2300%, no more than about 2250%, no more
than about 2200%, no more than about 2150%, no more than about
2100%, no more than about 2050%, no more than about 2000%, no more
than about 1950%, no more than about 1900%, no more than about
1850%, no more than about 1800%, no more than about 1750%, no more
than about 1700%, no more than about 1650%, no more than about
1600%, no more than about 1550%, no more than about 1500%, no more
than about 1450%, no more than about 1400%, no more than about
1350%, no more than about 1300%, no more than about 1250%, no more
than about 1200%, no more than about 1150%, no more than about
1100%, no more than about 1050%, no more than about 1000%, no more
than about 950%, no more than about 900%, no more than about 850%,
no more than about 800%, no more than about 750%, no more than
about 700%, no more than about 650%, no more than about 600%, no
more than about 550%, no more than about 500%, no more than about
450%, no more than about 445%, no more than about 440%, no more
than about 435%, no more than 430%, no more than about 425%, no
more than about 420%, no more than about 415%, no more than about
410%, no more than about 405%, no more than about 400%, no more
than about 395%, no more than about 390%, no more than about 385%,
no more than about 380%, no more than about 375%, no more than
about 370%, no more than about 365%, no more than about 360%, no
more than about 355%, no more than about 350%, no more than about
345%, no more than about 340%, no more than about 335%, no more
than 330%, no more than about 325%, no more than about 320%, no
more than about 315%, no more than about 310%, no more than about
305%, or no more than about 300%, no more than about 295%, no more
than about 290%, no more than about 285%, no more than about 280%,
no more than about 275%, no more than about 270%, no more than
about 265%, no more than about 260%, no more than about 255%, no
more than about 250%, no more than about 245%, no more than about
240%, no more than about 235%, no more than 230%, no more than
about 225%, no more than about 220%, no more than about 216%, no
more than about 215%, no more than about 210%, no more than about
205%, no more than about 200%, no more than about 195%, no more
than about 190%, no more than about 185%, no more than about 180%,
no more than about 175%, no more than about 170%, no more than
about 165%, no more than about 160%, no more than about 155%, no
more than about 150%, no more than about 145%, no more than about
140%, no more than about 135%, no more than about 130%, no more
than about 125%, no more than about 120%, no more than about 115%,
no more than about 110%, no more than about 105%, or no more than
about 100% of the normal baseline AUC of the CYP3A4 substrate drug,
inclusive of all ranges and subranges therebetween. In particular
embodiments, the CYP3A4 substrate drug is ranolazine, and the AUC
of ranolazine is maintained at a level of no more than about 150%
of the normal baseline AUC of ranolazine. In other particular
embodiments, the CYP3A4 substrate drug is lurasidone, and the AUC
of lurasidone is maintained at a level of no more than about 216%
of the normal baseline AUC of lurasidone. In other particular
embodiments, the CYP3A4 substrate drug is tadalafil, and the AUC of
tadalafil is maintained at a level of no more than about 410% of
the normal baseline AUC of tadalafil. In other particular
embodiments, the CYP3A4 substrate drug is tadalafil, and the AUC of
tadalafil is maintained at a level of no more than about 260% of
the normal baseline AUC of tadalafil. In other particular
embodiments, the CYP3A4 substrate drug is tadalafil, and the AUC of
tadalafil is maintained at a level of no more than about 207% of
the normal baseline AUC of tadalafil. In other particular
embodiments, the CYP3A4 substrate drug is erlotinib, and the AUC of
erlotinib is maintained at a level of no more than about 164% of
the normal baseline AUC of erlotinib. In other particular
embodiments, the CYP3A4 substrate drug is solifenacin succinate,
and the AUC of solifenacin succinate is maintained at a level of no
more than about 270% of the normal baseline AUC of solifenacin
succinate. In other particular embodiments, the CYP3A4 substrate
drug is everolimus, and the AUC of everolimus is maintained at a
level of no more than about 440% of the normal baseline AUC of
everolimus.
[0165] In various embodiments, the present disclosure also provides
for methods of treating patients previously treated with
posaconazole, with a CYP3A4 substrate drug which is contraindicated
for concomitant use with a strong CYP3A4 inhibitor, such as
posaconazole, wherein the CYP3A4 substrate drug maintains a
C.sub.max which is no more than about 4000% of the normal baseline
C.sub.max of the CYP3A4 substrate drug, e.g., 3950%, no more than
about 3900%, no more than about 3850%, no more than about 3800%, no
more than about 3750%, no more than about 3700%, no more than about
3650%, no more than about 3600%, no more than about 3550%, no more
than about 3500%, no more than about 3450%, no more than about
3400%, no more than about 3350%, no more than about 3300%, no more
than about 3250%, no more than about 3200%, no more than about
3150%, no more than about 3100%, no more than about 3050%, no more
than about 3000%, no more than about 2950%, no more than about
2900%, no more than about 2850%, no more than about 2800%, no more
than about 2750%, no more than about no more than about 2700%, no
more than about 2650%, no more than about 2600%, no more than about
2550%, no more than about 2500%, no more than about 2450%, no more
than about 2400%, no more than about 2350%, no more than about
2300%, no more than about 2250%, no more than about 2200%, no more
than about 2150%, no more than about 2100%, no more than about
2050%, no more than about 2000%, no more than about 1950%, no more
than about 1900%, no more than about 1850%, no more than about
1800%, no more than about 1750%, no more than about 1700%, no more
than about 1650%, no more than about 1600%, no more than about
1550%, no more than about 1500%, no more than about 1450%, no more
than about 1400%, no more than about 1350%, no more than about
1300%, no more than about 1250%, no more than about 1200%, no more
than about 1150%, no more than about 1100%, no more than about
1050%, no more than about 1000%, no more than about 950%, no more
than about 900%, no more than about 850%, no more than about 800%,
no more than about 750%, no more than about 700%, no more than
about 650%, no more than about 600%, no more than about 550%, no
more than about 500%, no more than about 450%, no more than about
445%, no more than about 440%, no more than about 435%, no more
than 430%, no more than about 425%, no more than about 420%, no
more than about 415%, no more than about 410%, no more than about
405%, no more than about 400%, no more than about 395%, no more
than about 390%, no more than about 385%, no more than about 380%,
no more than about 375%, no more than about 370%, no more than
about 365%, no more than about 360%, no more than about 355%, no
more than about 350%, no more than about 345%, no more than about
340%, no more than about 335%, no more than 330%, no more than
about 325%, no more than about 320%, no more than about 315%, no
more than about 310%, no more than about 305%, or no more than
about 300%, no more than about 295%, no more than about 290%, no
more than about 285%, no more than about 280%, no more than about
275%, no more than about 270%, no more than about 265%, no more
than about 260%, no more than about 255%, no more than about 250%,
no more than about 245%, no more than about 240%, no more than
about 235%, no more than 230%, no more than about 225%, no more
than about 220%, no more than about 216%, no more than about 215%,
no more than about 210%, no more than about 205%, no more than
about 200%, no more than about 195%, no more than about 190%, no
more than about 185%, no more than about 180%, no more than about
175%, no more than about 170%, no more than about 165%, no more
than about 160%, no more than about 155%, no more than about 150%,
no more than about 145%, no more than about 140%, no more than
about 135%, no more than about no 130%, no more than about 125%, no
more than about 120%, no more than about 115%, no more than about
110%, no more than about 105%, or no more than about 100% inclusive
of all ranges and subranges therebetween. In particular
embodiments, the CYP3A4 substrate drug is ranolazine, and the
C.sub.max of ranolazine is maintained at a level of no more than
about 150% of the normal baseline C.sub.max of ranolazine. As used
herein, the "normal baseline C.sub.max of ranolazine" refers to the
steady state C.sub.max measured for a particular dose of ranolazine
in the absence of other drugs. In some embodiments, the steady
state C.sub.max (% CV) is 1081 (49.1%) ng/mL measured after
administration of 500 mg ranolazine. In some embodiments, the
steady state C.sub.max (% CV) is 1955 (54.0%) ng/mL measured after
administration of 1,000 mg ranolazine. In other particular
embodiments, the CYP3A4 substrate drug is lurasidone, and the
C.sub.max of lurasidone is maintained at a level of no more than
about 210% of the normal baseline C.sub.max of lurasidone. As used
herein, the "normal baseline C.sub.max of lurasidone" refers to the
mean C.sub.max measured for a particular dose of lurasidone in the
absence of other drugs. In some embodiments, the mean C.sub.max (%
CV) is about 160 ng/mL measured after administration of 120 mg
lurasidone in the fed state following a 350 kcal meal. In other
particular embodiments, the CYP3A4 substrate drug is tadalafil, and
the C.sub.max of tadalafil is maintained at a level of no more than
about 120% of the normal baseline C.sub.max of tadalafil. As used
herein, the "normal baseline C.sub.max of tadalafil" refers to the
mean C.sub.max measured for a particular dose of tadalafil in the
absence of other drugs. In some embodiments, the mean C.sub.max (%
CV) is 190 (21.7%) .mu.g/L measured after administration of 10 mg
tadalafil. In some embodiments, the mean C.sub.max (% CV) is 548
(24.0%) .mu.g/L measured after administration of 20 mg tadalafil.
In other particular embodiments, the CYP3A4 substrate drug is
erlotinib, and the C.sub.max of erlotinib is maintained at a level
of no more than about 167% of the normal baseline C.sub.max of
erlotinib at 150 mg. As used herein, the "normal baseline C.sub.max
of erlotinib" refers to the mean C.sub.max measured at steady state
conditions for a particular dose of erlotinib in the absence of
other drugs. In some embodiments, the mean C.sub.max (% CV) is 1.7
(90%) .mu.g/mL measured after administration of 150 mg erlotinib.
The C.sub.max of erlotinib is highly variable and tends to increase
in cancer patients relative to healthy volunteers. Thus, in some
embodiments, the mean AUC.sub.0-24 (% CV) can range from about 1
.mu.g*h/mL to about 35 .mu.g*h/mL, e.g., about 2 .mu.g*h/mL, about
3 .mu.g*h/mL, about 4 .mu.g*h/mL, about 5 .mu.g*h/mL, about 6
.mu.g*h/mL, about 7 .mu.g*h/mL, about 8 .mu.g*h/mL, about 9
.mu.g*h/mL, about 10 .mu.g*h/mL, about 11 .mu.g*h/mL, about 12
.mu.g*h/mL, about 13 .mu.g*h/mL, about 14 .mu.g*h/mL, about 15
.mu.g*h/mL, about 16 .mu.g*h/mL, about 17 .mu.g*h/mL, about 18
.mu.g*h/mL, about 19 .mu.g*h/mL, about 20 .mu.g*h/mL, about 21
.mu.g*h/mL, about 22 .mu.g*h/mL, about 23 .mu.g*h/mL, about 24
.mu.g*h/mL, about 25 .mu.g*h/mL, about 27 .mu.g*h/mL, about 28
.mu.g*h/mL, about 29 .mu.g*h/mL, about 30 .mu.g*h/mL, about 31
.mu.g*h/mL, about 32 .mu.g*h/mL, about 33 .mu.g*h/mL, about 34
.mu.g*h/mL, inclusive of all values and subranges therebetween. In
other particular embodiments, the CYP3A4 substrate drug is
solifenacin succinate, and the C.sub.max of solifenacin succinate
is maintained at a level of no more than about 150% of the normal
baseline C.sub.max of solifenacin succinate. As used herein, the
"normal baseline C.sub.max of solifenacin" refers to the mean
C.sub.max measured at steady state conditions for a particular dose
of solifenacin succinate in the absence of other drugs. In some
embodiments, the mean C.sub.max (% CV) is 24.01 (30%) ng/mL
measured after administration of 5 mg solifenacin. In some
embodiments, the mean C.sub.max (% CV) is 40.61 (21%) ng/mL
measured after administration of 10 mg solifenacin succinate. In
other particular embodiments, the CYP3A4 substrate drug is
everolimus, and the C.sub.max of everolimus is maintained at a
level of no more than about 200% of the normal baseline C.sub.max
of everolimus. As used herein, the "normal baseline C.sub.max of
everolimus" refers to the mean C.sub.max measured at steady state
conditions for a particular dose of everolimus in the absence of
other drugs. In some embodiments, the mean C.sub.max (% CV) is
59.7.+-.16.9 (21.7%) ng/mL measured after administration of 10 mg
everolimus
[0166] In various other embodiments, the present disclosure
provides for methods of treating patients previously on
posaconazole with a reduced dose of a CYP3A4 substrate drug (e.g.,
about 10%-50% of the reference dose) which is contraindicated for
concomitant use with a strong CYP3A4 inhibitor, wherein the CYP3A4
substrate drug is maintained at a dose which provides a C.sub.max
which is no more than about 4000% of the normal baseline C.sub.max
of the CYP3A4 substrate drug for a period of at least about 2 to at
least about 21 days after stopping posaconazole treatment, e.g.,
3950%, no more than about 3900%, no more than about 3850%, no more
than about 3800%, no more than about 3750%, no more than about
3700%, no more than about 3650%, no more than about 3600%, no more
than about 3550%, no more than about 3500%, no more than about
3450%, no more than about 3400%, no more than about 3350%, no more
than about 3300%, no more than about 3250%, no more than about
3200%, no more than about 3150%, no more than about 3100%, no more
than about 3050%, no more than about 3000%, no more than about
2950%, no more than about 2900%, no more than about 2850%, no more
than about 2800%, no more than about 2750%, no more than about no
more than about 2700%, no more than about 2650%, no more than about
2600%, no more than about 2550%, no more than about 2500%, no more
than about 2450%, no more than about 2400%, no more than about
2350%, no more than about 2300%, no more than about 2250%, no more
than about 2200%, no more than about 2150%, no more than about
2100%, no more than about 2050%, no more than about 2000%, no more
than about 1950%, no more than about 1900%, no more than about
1850%, no more than about 1800%, no more than about 1750%, no more
than about 1700%, no more than about 1650%, no more than about
1600%, no more than about 1550%, no more than about 1500%, no more
than about 1450%, no more than about 1400%, no more than about
1350%, no more than about 1300%, no more than about 1250%, no more
than about 1200%, no more than about 1150%, no more than about
1100%, no more than about 1050%, no more than about 1000%, no more
than about 950%, no more than about 900%, no more than about 850%,
no more than about 800%, no more than about 750%, no more than
about 700%, no more than about 650%, no more than about 600%, no
more than about 550%, no more than about 500%, no more than about
450%, no more than about 445%, no more than about 440%, no more
than about 435%, no more than 430%, no more than about 425%, no
more than about 420%, no more than about 415%, no more than about
410%, no more than about 405%, no more than about 400%, no more
than about 395%, no more than about 390%, no more than about 385%,
no more than about 380%, no more than about 375%, no more than
about 370%, no more than about 365%, no more than about 360%, no
more than about 355%, no more than about 350%, no more than about
345%, no more than about 340%, no more than about 335%, no more
than 330%, no more than about 325%, no more than about 320%, no
more than about 315%, no more than about 310%, no more than about
305%, or no more than about 300%, no more than about 295%, no more
than about 290%, no more than about 285%, no more than about 280%,
no more than about 275%, no more than about 270%, no more than
about 265%, no more than about 260%, no more than about 255%, no
more than about 250%, no more than about 245%, no more than about
240%, no more than about 235%, no more than 230%, no more than
about 225%, no more than about 220%, no more than about 216%, no
more than about 215%, no more than about 210%, no more than about
205%, no more than about 200%, no more than about 195%, no more
than about 190%, no more than about 185%, no more than about 180%,
no more than about 175%, no more than about 170%, no more than
about 165%, no more than about 160%, no more than about 155%, no
more than about 150%, no more than about 145%, no more than about
140%, no more than about 135%, no more than about 130%, no more
than about 125%, no more than about 120%, no more than about 115%,
no more than about 110%, no more than about 105%, or no more than
about 100% inclusive of all ranges and subranges therebetween. In
particular embodiments, the CYP3A4 substrate drug is ranolazine,
and the C.sub.max of ranolazine is maintained at a level of no more
than about 150% of the normal baseline C.sub.max of ranolazine. In
other particular embodiments, the CYP3A4 substrate drug is
lurasidone, and the C.sub.max of lurasidone is maintained at a
level of no more than about 210% of the normal baseline C.sub.max
of lurasidone. In other particular embodiments, the CYP3A4
substrate drug is tadalafil, and the C.sub.max of tadalafil is
maintained at a level of no more than about 120% of the normal
baseline C.sub.max of tadalafil. In other particular embodiments,
the CYP3A4 substrate drug is erlotinib, and the C.sub.max erlotinib
is maintained at a level of no more than about 167% of the normal
baseline C.sub.max of erlotinib. In other particular embodiments,
the CYP3A4 substrate drug is solifenacin succinate, and the
C.sub.max of solifenacin succinate is maintained at a level of no
more than about 150% of the normal baseline C.sub.max of
solifenacin succinate. In other particular embodiments, the CYP3A4
substrate drug is everolimus, and the C.sub.max of everolimus is
maintained at a level of no more than about 200% of the normal
baseline C.sub.max of everolimus.
[0167] In embodiments in which the CYP3A4 substrate drug is
ranolazine, the daily dose of ranolazine is no more than about 500
mg, e.g., about 490 mg, about 480 mg, about 470 mg, about 460 mg,
about 450 mg, about 440 mg, about 430 mg, about 420 mg, about 410
mg, about 400 mg, about 390 mg, about 380 mg, about 370 mg, 360 mg,
about 350 mg, about 340 mg, about 330 mg, about 320 mg, about 310
mg, about 300 mg, about 290 mg, about 280 mg, about 270 mg, 260 mg,
about 250 mg, about 240 mg, about 230 mg, about 220 mg, about 210
mg, about 100 mg, about 190 mg, about 180 mg, about 170 mg, 160 mg,
about 150 mg, about 140 mg, about 130 mg, about 120 mg, about 110
mg, about 100 mg, about 90 mg, about 80 mg, about 70 mg, about 60
mg, or about 50 mg, inclusive of all values and ranges
therebetween, and treatment is delayed for at least about 2-21 days
after discontinuation of the posaconazole regimen, or reduced for
the time period of about 2-21 days after discontinuation of the
posaconazole regimen.
[0168] In embodiments in which the CYP3A4 substrate drug is
lurasidone, the daily dose of lurasidone is no more than about 80
mg, e.g., about 75, about 70 mg, about 65 mg, about 60 mg, about 55
mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30
mg, about 25 mg, about 20 mg, about 15 mg, or about 10 mg,
inclusive of all values and ranges therebetween, and treatment is
delayed for at least about 2-21 days after discontinuation of the
posaconazole regimen, or reduced for the time period of about 2-21
days after discontinuation of the posaconazole regimen.
[0169] In embodiments in which the CYP3A4 substrate drug is
tadalafil, the daily dose of tadalafil is no more than about 2.5
mg, e.g., about 2.25 mg, about 2.0 mg, about 1.75 mg, about 1.5 mg,
about 1.25 mg, about 1.0 mg, about 0.75 mg, or about 0.5 mg,
inclusive of all values and ranges therebetween, and treatment is
delayed for at least about 2-21 days after discontinuation of the
posaconazole regimen, or reduced for the time period of about 2-21
days after discontinuation of the posaconazole regimen.
[0170] In other embodiments in which the CYP3A4 substrate drug is
tadalafil, the 72 hr dose of tadalafil is no more than about 10 mg,
e.g., about 9.5 mg, about 9.0 mg, about 8.5 mg, about 8.0 mg, about
7.5 mg, about 7.0 mg, about 6.5 mg, about 6.0 mg, about 5.5 mg,
about 5.0 mg, about 4.5 mg, about 4.0 mg, about 3.5 mg, about 3.0
mg, about 2.5 mg, about 2.0 mg, about 1.5 mg, about 1.0 mg, or
about 0.5 mg, inclusive of all values and ranges therebetween, and
treatment is delayed for at least about 2-21 days after
discontinuation of the posaconazole regimen, or reduced for the
time period of about 2-21 days after discontinuation of the
posaconazole regimen.
[0171] In embodiments in which the CYP3A4 substrate drug is
erlotinib, the daily dose of erlotinib is no more than about 150
mg, e.g., about 140 mg, about 130 mg, about 120 mg, about 110 mg,
about 100 mg, about 90 mg, about 80 mg, about 70 mg, about 60 mg,
about 50 mg, about 40 mg, about 30 mg, about 20 mg, or about 10 mg,
inclusive of all values and ranges therebetween, and treatment is
delayed for at least about 2-21 days after discontinuation of the
posaconazole regimen, or reduced for the time period of about 2-21
days after discontinuation of the posaconazole regimen.
[0172] In embodiments in which the CYP3A4 substrate drug is
solifenacin succinate, the daily dose of solifenacin succinate is
no more than about 10 mg, e.g., about 9 mg, about 8 mg, about 7 mg,
about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1
mg, or about 0.5 mg, inclusive of all values and ranges
therebetween, and treatment is delayed for at least about 2-21 days
after discontinuation of the posaconazole regimen, or reduced for
the time period of about 2-21 days after discontinuation of the
posaconazole regimen.
[0173] In embodiments in which the CYP3A4 substrate drug is
everolimus, the daily dose of everolimus is no more than about 10
mg, e.g., about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5
mg, about 4 mg, about 3 mg, about 2 mg, about 1.75 mg, about 1.5
mg, about 1.25 mg, about 1.0 mg, about 0.75 mg, or about 0.5 mg,
inclusive of all values and ranges therebetween, and treatment is
delayed for at least about 2-21 days after discontinuation of the
posaconazole regimen, or reduced for the time period of about 2-21
days after discontinuation of the posaconazole regimen.
[0174] In embodiments in which the CYP3A4 substrate drug is
abemaciclib, the daily dose of abemaciclib is no more than about
400 mg, e.g., about 350 mg, about 300 mg, about 250 mg, about 225
mg, about 200 mg, about 175 mg, about 150 mg, about 125 mg, about
100 mg, about 75 mg, about 50 mg, about 25 mg, about 10 mg, about 5
mg, about 1.0 mg, or about 0.5 mg, inclusive of all values and
ranges therebetween, and treatment is delayed for at least about
2-21 days after discontinuation of the posaconazole regimen, or
reduced for the time period of about 2-21 days after
discontinuation of the posaconazole regimen.
[0175] In embodiments in which the CYP3A4 substrate drug is
ivacaftor, the daily dose of ivacaftor is no more than about 300
mg, e.g., about 250 mg, about 225 mg, about 200 mg, about 175 mg,
about 150 mg, about 125 mg, about 100 mg, about 75 mg, about 50 mg,
about 25 mg, about 10 mg, about 5 mg, about 1.0 mg, or about 0.5
mg, inclusive of all values and ranges therebetween, and treatment
is delayed for at least about 2-21 days after discontinuation of
the posaconazole regimen, or reduced for the time period of about
2-21 days after discontinuation of the posaconazole regimen.
[0176] In embodiments in which the CYP3A4 substrate drug is
ruxolitinib, or a pharmaceutically acceptable salt thereof (e.g.,
ruxolitinib phosphate), the daily dose of ruxolitinib phosphate is
no more than about 50 mg, e.g., about 48 mg, about 45 mg, about 40
mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15
mg, about 10 mg, about 5 mg, about about 1.0 mg, about 0.75 mg, or
about 0.5 mg, inclusive of all values and ranges therebetween, and
treatment is delayed for at least about 2-21 days after
discontinuation of the posaconazole regimen, or reduced for the
time period of about 2-21 days after discontinuation of the
posaconazole regimen.
[0177] In embodiments in which the CYP3A4 substrate drug is
brexpiprazole, the daily dose of brexpiprazole is no more than
about 4 mg, e.g., about 3 mg, about 2 mg, about 1.75 mg, about 1.5
mg, about 1.25 mg, about 1.0 mg, about 0.75 mg, or about 0.5 mg,
inclusive of all values and ranges therebetween, and treatment is
delayed for at least about 2-21 days after discontinuation of the
posaconazole regimen, or reduced for the time period of about 2-21
days after discontinuation of the posaconazole regimen.
[0178] In embodiments in which the CYP3A4 substrate drug is
ivacaftor/tezacaftor, the daily dose of tezactaftor is no more than
about 100 mg, e.g., about 90 mg, about 80 mg, about 70 mg, about 60
mg, about 50 mg, about 40 mg, about 30 mg, about 20 mg, about 17.5
mg, about 15 mg, about 12.5 mg, about 10 mg, about 7.5 mg, or about
5 mg, inclusive of all values and ranges therebetween, and the
daily dose of ivacaftor is no more than about 300 mg, e.g., about
290 mg, about 280 mg, about 270 mg, about 260 mg, about 250 mg,
about 240 mg, about 230 mg, about 220 mg, about 175 mg, about 150
mg, about 125 mg, about 100 mg, about 75 mg, or about 50 mg,
inclusive of all values and ranges therebetween, and treatment is
delayed for at least about 2-21 days after discontinuation of the
posaconazole regimen, or reduced for the time period of about 2-21
days after discontinuation of the posaconazole regimen.
[0179] In embodiments in which the CYP3A4 substrate drug is
regorafenib, the daily dose of regorafenib is no more than about
160 mg, e.g., about 150 mg, about 140 mg, about 130 mg, about 120
mg, about 110 mg, about 100 mg, about 90 mg, about 80 mg, about 70
mg, about 60 mg, about 50 mg, about 25 mg, about 10 mg, or about 5
mg, inclusive of all values and ranges therebetween, and treatment
is delayed for at least about 2-21 days after discontinuation of
the posaconazole regimen, or reduced for the time period of about
2-21 days after discontinuation of the posaconazole regimen.
[0180] In embodiments in which the CYP3A4 substrate drug is
daclatasvir, the daily dose of daclatasvir is no more than about 90
mg, e.g., about 80 mg, about 70 mg, about 60 mg, about 50 mg, about
40 mg, about 30 mg, about 20 mg, about 17.5 mg, about 15 mg, about
12.5 mg, about 10 mg, about 7.5 mg, or about 5 mg, inclusive of all
values and ranges therebetween, and treatment is delayed for at
least about 2-21 days after discontinuation of the posaconazole
regimen, or reduced for the time period of about 2-21 days after
discontinuation of the posaconazole regimen.
[0181] In embodiments in which the CYP3A4 substrate drug is
crizotinib, the daily dose of crizotinib is no more than about 500
mg, e.g., about 450 mg, about 400 mg, about 350 mg, about 300 mg,
about 250 mg, about 225 mg, about 200 mg, about 175 mg, about 150
mg, about 125 mg, about 100 mg, about 75 mg, about 50 mg, about 25
mg, about 10 mg, about 5 mg, about 1.0 mg, or about 0.5 mg,
inclusive of all values and ranges therebetween, and treatment is
delayed for at least about 2-21 days after discontinuation of the
posaconazole regimen, or reduced for the time period of about 2-21
days after discontinuation of the posaconazole regimen.
[0182] In embodiments in which the CYP3A4 substrate drug is
naloxegol or a pharmaceutically acceptable salt thereof (e.g.,
naloxegol oxalate), the daily dose of naloxegol oxalate is no more
than about 25 mg, e.g., about 22 mg, about 20 mg, about 18 mg,
about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12 mg,
about 10 mg, about 8 mg, about 5 mg, about 1 mg, about 0.75 mg, or
about 0.5 mg, inclusive of all values and ranges therebetween, and
treatment is delayed for at least about 2-21 days after
discontinuation of the posaconazole regimen, or reduced for the
time period of about 2-21 days after discontinuation of the
posaconazole regimen.
[0183] In embodiments in which the CYP3A4 substrate drug is
dabrafenib, the daily dose of dabrafenib is no more than about 300
mg, e.g., about 250 mg, about 225 mg, about 200 mg, about 175 mg,
about 150 mg, about 125 mg, about 100 mg, about 75 mg, about 50 mg,
about 25 mg, about 10 mg, about 5 mg, about 1.0 mg, or about 0.5
mg, inclusive of all values and ranges therebetween, and treatment
is delayed for at least about 2-21 days after discontinuation of
the posaconazole regimen, or reduced for the time period of about
2-21 days after discontinuation of the posaconazole regimen.
[0184] In embodiments in which the CYP3A4 substrate drug is
elbasvir and grazoprevir, the daily dose of elbasvir is no more
than about 1000 mg, e.g., about 900 mg, about 800 mg, about 700 mg,
about 600 mg, about 500 mg, about 400 mg, about 300 mg, about 200
mg, about 175 mg, about 150 mg, about 125 mg, about 100 mg, about
75 mg, about 50 mg, or about 25 mg, inclusive of all values and
ranges therebetween, and the daily dose of grazoprevir is no more
than about 2000 mg, e.g., about 1500 mg, about 1250 mg, about 1000
mg, about 900 mg, about 800 mg, about 700 mg, about 600 mg, about
500 mg, about 400 mg, about 300 mg, about 200 mg, about 150 mg,
about 100 mg, about 75 mg, or about 50 mg, inclusive of all values
and ranges therebetween, and treatment is delayed for at least
about 2-21 days after discontinuation of the posaconazole regimen,
or reduced for the time period of about 2-21 days after
discontinuation of the posaconazole regimen.
[0185] In some embodiments, the time period for delaying treatment
of the CYP3A4 substrate drug, or the time period during which the
patient is treated with a reduced dose (e.g., no more than about
90%, about 75%, about 50%, about 25%, etc. of the reference dose)
of the CYP3A4 substrate, is at least about 1.5 times the reported
average t.sub.1/2 of posaconazole, e.g., about 2 times, about 2.5
times, about 3 times, about 3.5 times, about 4 times, about 4.5
times, about 5 times, about 5.5 times, about 6 times, about 6.5
times, about 7 times, about 7.5 times, about 8 times, about 8.5
times, about 9 times, about 9.5 times, about 10 times, inclusive of
all values and subranges therebetween.
[0186] The present disclosure also provides methods for treating,
or prescribing treatment, with a CYP3A4 substrate drug intended to
treat any of the disorders or conditions described herein, to a
patient who has been administered posaconazole prior to the
administration of the CYP3A4 substrate drug. In addition to
treating the disorder or condition treatable with the CYP3A4
substrate drug, in some embodiments the methods of the present
invention reduce the severity or incidence of side effects
associated with administration of the CYP3A4 substrate drug after
stopping administration of posaconazole. In embodiments, these
methods include (a) treating a patient with multiple doses of
posaconazole, (b) not administering the CYP3A4 substrate drug
during the administration of the posaconazole regimen, (c) stopping
administration of posaconazole, (d) delaying treatment of a CYP3A4
substrate drug, or prescribing treatment of the CYP3A4 substrate
drug to be delayed, for at least 2-21 days after stopping the
posaconazole regimen, and then (e) treating with a CYP3A4 substrate
drug. In other embodiments, the methods include (a) treating a
patient with multiple doses of posaconazole, (b) not treating the
patient with the CYP3A4 substrate drug during the posaconazole
regimen, (c) stopping the posaconazole regimen; and (d) for at
least about 2-21 days after stopping the posaconazole regimen,
treating the patient with the CYP3A4 substrate drug at a dose which
is no more than about 50% of the reference dose of the CYP3A4
substrate drug (e.g., an amount in the range of about 10% to about
50%, or about 10% to about 90%, of the reference dose, as described
above). The disease or condition treated with the CYP3A4 substrate
drug can include any disease or condition described herein or for
which CYP3 substrate drug is administered. In some embodiments, the
disease or condition is selected from the group consisting of
schizophrenia in adults and adolescents (13 to 17 years),
depressive episodes associated with Bipolar I Disorder (bipolar
depression) in adults, as monotherapy or as adjunctive therapy with
lithium or valproate, chronic angina, erectile dysfunction (ED),
benign prostatic hyperplasia (BPH), and pulmonary arterial
hypertension (PAH) (WHO Group 1) to improve exercise ability. In
other embodiments, the disease or condition is selected from the
group consisting of non-small cell lung cancer (NSCLC) whose
disease has not progressed after four cycles of platinum-based
first-line chemotherapy, locally advanced or metastatic NSCLC after
failure of at least one prior chemotherapy regimen, locally
advanced, unresectable or metastatic pancreatic cancer, overactive
bladder with symptoms of urge urinary incontinence, urgency, and
urinary frequency, advanced renal cell carcinoma (RCC) after
failure of treatment with sunitinib or sorafenib, subependymal
giant cell astrocytoma (SEGA) associated with tuberous sclerosis
(TS) who require therapeutic intervention but are not candidates
for curative surgical resection, renal angiomyolipoma, and tuberous
sclerosis complex. In other embodiments, the disease or condition
is selected from the group consisting of in combination with
fulvestrant for the treatment of women with hormone receptor
(HR)-positive, human epidermal growth factor receptor 2
(HER2)-negative advanced or metastatic breast cancer with disease
progression following endocrine therapy, as monotherapy for the
treatment of adult patients with HRpositive, HER2-negative advanced
or metastatic breast cancer with disease progression following
endocrine therapy and prior chemotherapy in the metastatic setting,
cystic fibrosis (CF) in patients age 2 years and older who have one
mutation in the CFTR gene that is responsive to ivacaftor based on
clinical and/or in vitro assay data, deleterious or suspected
deleterious germline BRCA-mutated advanced ovarian cancer in adult
patients who have been treated with three or more prior lines of
chemotherapy, intermediate or high-risk myelofibrosis, including
primary myelofibrosis, post-polycythemia vera myelofibrosis and
post-essential thrombocythemia myelofibrosis, polycythemia vera
patients who have had an inadequate response to or are intolerant
of hydroxyurea, as an adjunctive therapy to antidepressants for the
treatment of major depressive disorder (MDD), schizophrenia, cystic
fibrosis (CF) patients aged 12 years and older who are homozygous
for the F508del mutation or who have at least one mutation in the
cystic fibrosis transmembrane conductance regulator (CFTR) gene
that is responsive to tezacaftor/ivacaftor based on in vitro data
and/or clinical evidence, metastatic colorectal cancer (CRC)
patients who have been previously treated with fluoropyrimidine-,
oxaliplatin- and irinotecan-based chemotherapy, an antiVEGF
therapy, and, if RAS wild-type, an anti-EGFR therapy, locally
advanced, unresectable or metastatic gastrointestinal stromal tumor
(GIST) patients who have been previously treated with imatinib
mesylate and sunitinib malate, hepatocellular carcinoma (HCC) who
have been previously treated with sorafenib, use with sofosbuvir,
with or without ribavirin, for the treatment of chronic HCV
genotype 1 or 3 infection, metastatic non-small cell lung cancer
(NSCLC) patients whose tumors are anaplastic lymphoma kinase (ALK)
or ROS1-positive as detected by an FDA-approved test, opioid
induced constipation (OIC) in adult patients with chronic
non-cancer pain, including patients with chronic pain related to
prior cancer or its treatment who do not require frequent (e.g.,
weekly) opioid dosage escalation, unresectable or metastatic
melanoma with BRAF V600E mutation as detected by an FDA-approved
test, in combination with trametinib, for the treatment of patients
with unresectable or metastatic melanoma with BRAF V600E or V600K
mutations as detected by an FDA-approved test, adjuvant treatment
of patients with melanoma with BRAF V600E or V600K mutations, as
detected by an FDA-approved test, and involvement of lymph node(s),
following complete resection, metastatic non-small cell lung cancer
(NSCLC) with BRAF V600E mutation as detected by an FDA-approved
test, locally advanced or metastatic anaplastic thyroid cancer
(ATC) in patients with BRAF V600E mutation and with no satisfactory
locoregional treatment options, and with or without ribavirin for
treatment of chronic HCV genotypes 1 or 4 infection in adults. In
some embodiments, the time period for delaying administration of
the CYP3A4 substrate drug, or the time period during which the
CYP3A4 substrate drug is administered at no more than 50% of the
reference dose, is greater than about 21 days, such as 22, 23, 24,
25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,
42, 43, 44, or 45 days, e.g., for patients with one or more
physiological characteristics described herein.
[0187] Other particular embodiments are provided herein below:
[0188] 1. A method of treating a patient who has previously been
administered a therapeutically effective regimen of posaconazole,
with a CYP3A4 substrate drug contraindicated for concomitant
administration with a strong CYP3A4 inhibitor, said method
comprising:
[0189] first treating the patient, or prescribing a first treatment
to begin, with the CYP3A4 substrate drug at least 2-21 days after
stopping administration of posaconazole.
[0190] 2. The method of embodiment 1, wherein said CYP3A4 substrate
drug is selected from the group consisting of lurasidone,
ranolazine, lumacaftor/ivacaftor, venetoclax, trabectedin,
ribociclib succinate, deflazacort, cinacalcet hydrochloride,
pimavanserin tartrate, aripiprazole lauroxil, cariprazine
hydrochloride, simeprevir sodium, everolimus, saxagliptin
hydrochloride, saxagliptin/metformin hydrochloride, ticagrelor,
vilazodone hydrochloride, apixaban, tofacitinib citrate, eletriptan
hydrobromide, nilotinib hydrochloride monohydrate, dronedarone
hydrochloride, fluticasone propionate/salmeterol xinafoate,
rivaroxaban, tadalafil, ibrutinib, cobimetinib, colchicine,
cabazitaxel, tolvaptan, fosaprepitant dimeglumine, aprepitant,
solifenacin succinate, erlotinib hydrochloride, ado-trastuzumab
ematansine, bosutinib monohydrate, sunitinib malate, fesoterodine
fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,
axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate,
ponatinib hydrochloride, isavuconazonium sulfate, lomitapide
mesylate, iloperidone, palbociclib, levomilnacipran hydrochloride,
pimozide, pomalidomide, abemaciclib, ivacaftor, ruxolitinib
phosphate, brexpiprazole, ivacaftor/tezacaftor, regorafenib,
daclatasvir, crizotinib, naloxegol oxalate, dabrafenib, olaparib,
and elbasvir and grazoprevir.
[0191] 3. The method of embodiment 2, wherein the CYP3A4 substrate
drug is lurasidone.
[0192] 4. The method of embodiment 2, wherein the CYP3A4 substrate
drug is ranolazine.
[0193] 5. The method of embodiment 2, wherein the CYP3A4 substrate
drug is tadalafil.
[0194] 6. The method of any of embodiments 1-5, wherein the patient
is obese.
[0195] 7. The method of embodiment 6, wherein the patient has at
least one of the following characteristics:
[0196] i) BMI of at least about 35;
[0197] ii) % IBW of at least about 150%;
[0198] iii) waist size greater than about 42 inches;
[0199] iv) % body fat greater than about 40%;
[0200] v) total body fat greater than about 40 kg; and
[0201] vi) medically diagnosed as obese.
[0202] 8. The method of any of embodiments 1-7, wherein the CYP3A4
substrate drug is ranolazine, and the AUC of ranolazine is
maintained at a level of no more than about 150% of a normal
baseline AUC of ranolazine.
[0203] 9. The method of any of embodiments 1-7, wherein the CYP3A4
substrate drug is ranolazine, and the C.sub.max of ranolazine is
maintained at a level of no more than about 150% of a normal
baseline C.sub.max of ranolazine.
[0204] 10. The method of any of embodiments 1-7, wherein the CYP3A4
substrate drug is lurasidone, and the AUC of lurasidone is
maintained at a level of no more than about 216% of a normal
baseline AUC of lurasidone.
[0205] 11. The method of any of embodiments 1-7, wherein the CYP3A4
substrate drug is lurasidone, and the C.sub.max of lurasidone is
maintained at a level of no more than about 210% of a normal
baseline C.sub.max of lurasidone.
[0206] 12. The method of any of embodiments 1-7, wherein the CYP3A4
substrate drug is tadalafil, and the AUC of tadalafil is maintained
at a level of no more than about 410% of a normal baseline AUC of
tadalafil.
[0207] 13. The method of any of embodiments 1-7, wherein the CYP3A4
substrate drug is tadalafil, and the a C.sub.max of tadalafil is
maintained at a level of no more than about 120% of a normal
baseline C.sub.max of tadalafil.
[0208] 14. The method of embodiments 1-10, wherein the patient is a
poor or intermediate CYP3A4 metabolizer.
[0209] 15. A method of treating a patient with a CYP3A4 substrate
drug contraindicated for concomitant administration with a strong
CYP3A4 inhibitor, comprising:
[0210] treating or prescribing a therapeutically effective amount
of a CYP3A4 substrate drug to a patient in need thereof,
[0211] wherein:
said patient has previously been administered a therapeutically
effective regimen of posaconazole, and
[0212] for at least about 2-21 days after discontinuation of the
posaconazole regimen, said patient is treated with the CYP3A4
substrate drug is at a dose which is no more than about 50% of the
reference dose.
[0213] 16. The method of embodiment 15, wherein said CYP3A4
substrate drug is selected from the group consisting of lurasidone,
ranolazine, lumacaftor/ivacaftor, venetoclax, trabectedin,
ribociclib succinate, deflazacort, cinacalcet hydrochloride,
pimavanserin tartrate, aripiprazole lauroxil, cariprazine
hydrochloride, simeprevir sodium, everolimus, saxagliptin
hydrochloride, saxagliptin/metformin hydrochloride, ticagrelor,
vilazodone hydrochloride, apixaban, tofacitinib citrate, eletriptan
hydrobromide, nilotinib hydrochloride monohydrate, dronedarone
hydrochloride, fluticasone propionate/salmeterol xinafoate,
rivaroxaban, tadalafil, ibrutinib, cobimetinib, colchicine,
cabazitaxel, tolvaptan, fosaprepitant dimeglumine, aprepitant,
solifenacin succinate, erlotinib hydrochloride, ado-trastuzumab
ematansine, bosutinib monohydrate, sunitinib malate, fesoterodine
fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,
axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate,
ponatinib hydrochloride, isavuconazonium sulfate, lomitapide
mesylate, iloperidone, palbociclib, levomilnacipran hydrochloride,
pimozide, pomalidomide, abemaciclib, ivacaftor, ruxolitinib
phosphate, brexpiprazole, ivacaftor/tezacaftor, regorafenib,
daclatasvir, crizotinib, naloxegol oxalate, dabrafenib, olaparib,
and elbasvir and grazoprevir.
[0214] 17. The method of embodiment 16, wherein the CYP3A4
substrate drug is lurasidone.
[0215] 18. The method of embodiment 16, wherein the CYP3A4
substrate drug is ranolazine.
[0216] 19. The method of embodiment 16, wherein the CYP3A4
substrate drug is tadalafil.
[0217] 20. The method of any of embodiments 15-19, wherein the
patient is obese.
[0218] 21. The method of embodiment 20, wherein the patient has at
least one of the following characteristics:
[0219] i) BMI of at least about 35;
[0220] ii) % IBW of at least about 150%;
[0221] iii) waist size greater than about 42 inches;
[0222] iv) % body fat greater than about 40%;
[0223] v) total body fat greater than about 40 kg; and
[0224] vi) medically diagnosed as obese.
[0225] 22. The method of any of embodiments 15-21, wherein the
CYP3A4 substrate drug is ranolazine, and the AUC of ranolazine is
maintained at a level of no more than about a normal baseline AUC
of ranolazine to about 150% of the normal baseline AUC of
ranolazine.
[0226] 23. The method of any of embodiments 15-21, wherein the
CYP3A4 substrate drug is ranolazine, and the C.sub.max of
ranolazine is maintained at a level of no more than about a normal
baseline C.sub.max of ranolazine to about 150% of the normal
baseline C.sub.max of ranolazine.
[0227] 24. The method of any of embodiments 15-21, wherein the
CYP3A4 substrate drug is lurasidone, and the AUC of lurasidone is
maintained at a level of no more than about a normal baseline AUC
of lurasidone to about 216% of the normal baseline AUC of
lurasidone.
[0228] 25. The method of any of embodiments 15-21, wherein the
CYP3A4 substrate drug is lurasidone, and the C.sub.max of
lurasidone is maintained at a level of no more than about a normal
baseline C.sub.max of lurasidone to about 210% of the normal
baseline C.sub.max of lurasidone.
[0229] 26. The method of any of embodiments 15-21, wherein the
CYP3A4 substrate drug is tadalafil, and the AUC of tadalafil is
maintained at a level of no more than about 410% of a normal
baseline AUC of tadalafil.
[0230] 27. The method of any of embodiments 15-21, wherein the
CYP3A4 substrate drug is tadalafil, and the a C.sub.max of
tadalafil is maintained at a level of no more than about 120% of a
normal baseline C.sub.max of tadalafil.
[0231] 28. The method of embodiments 15-27, wherein the patient is
a poor or intermediate CYP3A4 metabolizer.
[0232] 29. The method of embodiment 15, wherein the CYP3A4
substrate drug is ranolazine and the daily dose is no more than
about 500 mg for at least about 2-21 days after discontinuation of
the posaconazole regimen.
[0233] 30. A method of treating a disease or condition in a patient
with a CYP3A4 substrate drug which is contraindicated for
concomitant use with a strong CYP3A4 inhibitor, wherein the patient
is also in need of treatment with posaconazole, comprising:
[0234] (a) treating a patient with a therapeutically effective
regimen of posaconazole;
[0235] (b) not treating the patient with the CYP3A4 substrate drug
during the posaconazole regimen, and for at least 2-21 days after
stopping the posaconazole regimen; and then
[0236] (c) treating, or prescribing treatment to begin, with a
therapeutically effective amount of the CYP3A4 substrate drug;
[0237] wherein the disease or condition treated with the CYP3A4
substrate drug is selected from the group consisting of
schizophrenia in adults and adolescents (13 to 17 years),
depressive episodes associated with Bipolar I Disorder (bipolar
depression) in adults, as monotherapy or as adjunctive therapy with
lithium or valproate, chronic angina, cystic fibrosis in patients 6
years and older who are homozygous for the F508del mutation in the
CFTR gene, chronic lymphocytic leukemia in patients with 17p
deletion, who have received at least one prior therapy,
unresectable or metastatic liposarcoma or leiomyosarcoma in
patients who received a prior anthracycline-containing regimen,
advanced or metastatic breast cancer in postmenopausal women with
hormone receptor (HR)-positive, human epidermal growth factor
receptor 2 (HER2)-negative advanced or metastatic breast cancer,
negative advanced or metastatic breast cancer in combination with
an aromatase inhibitor for postmenopausal women, Duchenne muscular
dystrophy (DMD), secondary hyperparathyroidism (HPT) in patients
with chronic kidney disease (CKD) on dialysis, hypercalcemia in
patients with parathyroid carcinoma or in patients with primary HPT
for who parathyroidectomy would be indicated on the basis of serum
calcium levels, but who are unable to undergo parathyroidectomy,
hallucinations and delusions associated with Parkinson's disease
psychosis, schizophrenia, acute manic or mixed episodes associated
with bipolar I disorder, chronic hepatitis C (CHC) infection as a
component of a combination antiviral treatment regimen with
peginterferon alfa and ribavirin in HCV genotype 1 infected
subjects with compensated liver disease, postmenopausal women with
advanced hormone receptor-positive, HER2-negative breast cancer
(advanced HR+ BC), e.g., in combination with exemestane after
failure of treatment with letrozole or anastrozole, progressive
neuroendocrine tumors of pancreatic origin (PNET), progressive,
well-differentiated, non-functional neuroendocrine tumors (NET) of
gastrointestinal (GI) or lung origin that are unresectable, locally
advanced or metastatic, advanced renal cell carcinoma (RCC), e.g.,
after failure of treatment with sunitinib or sorafenib, renal
angiomyolipoma and tuberous sclerosis complex (TSC), not requiring
immediate surgery, TSC in patients who have subependymal giant cell
astrocytoma (SEGA) that require therapeutic intervention but are
not candidates for surgical resection, type 2 diabetes mellitus in
adults as an adjunct to diet and exercise to improve glycemic
control, major depressive disorder (MDD), thrombotic cardiovascular
events (e.g., cardiovascular death, myocardial infarction, or
stroke) in patients with acute coronary syndrome (ACS), stroke and
systemic embolism in patients with nonvalvular atrial fibrillation,
deep vein thrombosis (DVT), which may lead to pulmonary embolism
(PE) in patients who have undergone hip or knee replacement
surgery, DVT, PE, recurrent DVT and PE following initial therapy,
moderate to severe active rheumatoid arthritis in patients who have
had inadequate response or tolerance to methotrexate, acute
migraine with or without aura, chronic phase and accelerated phase
Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML)
in newly diagnosed patients or in patients resistant to or
intolerant to prior therapy that included imatinib, atrial
fibrillation (AF) in patients with a history of paroxysmal or
persistant AF or atrial flutter (AFK), who are in sinus rhythm or
will be cardioverted, asthma in patients aged 4 years and older,
airflow obstruction and reducing exacerbations in patients with
chronic obstructive pulmonary disease, erectile dysfunction (ED),
benign prostatic hyperplasia (BPH), pulmonary arterial hypertension
(PAH) (WHO Group 1) to improve exercise ability, gout flares,
Familial Mediterranean fever antiretroviral therapy, anxiety
disorders, panic disorders, seizures, insomnia, hypertension,
cardiovascular disease, hyperlipidemia, cancer, such as primary
kidney cancer, advanced primary liver cancer, radioactive iodine
resistant advanced thyroid carcinoma, renal cell carcinoma,
imatinib-resistant gastrointestinal stromal tumor, mantle cell
lymphoma in patients who have received at least one prior therapy,
chronic lymphocytic leukemia/small lymphocytic lymphoma, chronic
lymphocytic leukemia/small lymphocytic lymphoma with 17p deletion,
Waldenstrom's macroglobulinemia, marginal zone lymphoma who require
systemic therapy and have received at least one prior
anti-CD20-based therapy, unresectable or metastatic melanoma with a
BRAF V600E or V600K mutation, allergies, transplantation,
hormone-refractory metastatic prostate cancer previously treated
with a docetaxel-containing treatment regimen, hormone-refractory
metastatic prostate cancer previously treated with a
docetaxel-containing treatment regimen, treatment of clinically
significant hypervolemic and euvolemic hyponatremia, including
patients with heart failure and Syndrome of Inappropriate
Antidiuretic Hormone (SIADH), prevention of acute and delayed
nausea and vomiting associated with initial and repeat courses of
highly emetogenic cancer chemotherapy (HEC) including high-dose
cisplatin, prevention of delayed nausea and vomiting associated
with initial and repeat courses of moderately emetogenic cancer
chemotherapy (MEC), over-active bladder with symptoms of urge
urinary incontinence, urgency, and urinary frequency, metastatic
non-small cell lung cancer (NSCLC) whose tumors have epidermal
growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R)
substitution mutations as detected by an FDA-approved test
receiving first-line, maintenance, or second or greater line
treatment after progression, locally advanced, unresectable or
metastatic pancreatic cancer, in combination with gemcitabine,
HER2-positive, metastatic breast cancer who previously received
trastuzumab and a taxane, separately or in combination in patients
who have either: received prior therapy for metastatic disease or
developed disease recurrence during or within six months of
completing adjuvant therapy, chronic, accelerated, or blast phase
Ph+ chronic myelogenous leukemia (CML) in adults with resistance or
intolerance to prior therapy, gastrointestinal stromal tumor (GIST)
after disease progression on or intolerance to imatinib mesylate,
advanced renal cell carcinoma (RCC), progressive,
well-differentiated pancreatic neuroendocrine tumors (pNET) in
patients with unresectable locally advanced or metastatic disease,
CCR5-tropic HIV-1 infection in patients 2 years of age and older
weighing at least 10 kg in combination with other antiretroviral
agents, advanced renal cell carcinoma, advanced soft tissue sarcoma
who have received prior chemotherapy, manic and mixed episodes
associated with Bipolar I, Major Depressive Disorder, irritability
associated with Autistic Disorder, Tourette's disorder, agitation
associated with schizophrenia or bipolar mania, advanced renal cell
carcinoma after failure of one prior systemic therapy, to improve
glycemic control in adults with type 2 diabetes mellitus (T2DM) who
have inadequate control with dapagliflozin or who are already
treated with dapagliflozin and saxagliptin, progressive, metastatic
medullary thyroid cancer (MTC), advanced renal cell carcinoma (RCC)
who have received prior anti-angiogenic therapy, chronic phase,
accelerated phase, or blast phase chronic myeloid leukemia (CML) or
Ph+ ALL in adults for whom no other tyrosine kinase inhibitor (TKI)
therapy is indicated, T315I-positive CML (chronic phase,
accelerated phase, or blast phase) or T315I-positive Philadelphia
chromosome in adults, positive acute lymphoblastic leukemia (Ph+
ALL), invasive aspergillosis, invasive mucormycosis, to reduce
low-density lipoprotein cholesterol (LDL-C), total cholesterol
(TC), apolipoprotein B (apo B), and non-high density lipoprotein
cholesterol (non-HDL-C) in patients with homozygous familial
hypercholesterolemia (HoFH), schizophrenia in adults, hormone
receptor (HR)-positive, human epidermal growth factor receptor 2
(HER2)-negative advanced or metastatic breast cancer in combination
with an aromatase inhibitor as initial endocrine based therapy in
postmenopausal women, or fulvestrant in women with disease
progression following endocrine therapy, Major Depressive Disorder
(MDD), suppression of motor and phonic tics in patients with
Tourette's Disorder who have failed to respond satisfactorily to
standard treatment, treatment of multiple myeloma in patients who
have received at least two prior therapies including lenalidomide
and a proteasome inhibitor and have demonstrated disease
progression on or within 60 days of completion of the last therapy,
non-small cell lung cancer (NSCLC) whose disease has not progressed
after four cycles of platinum-based first-line chemotherapy,
locally advanced or metastatic NSCLC after failure of at least one
prior chemotherapy regimen, locally advanced, unresectable or
metastatic pancreatic cancer, overactive bladder with symptoms of
urge urinary incontinence, urgency, and urinary frequency, advanced
renal cell carcinoma (RCC) after failure of treatment with
sunitinib or sorafenib, subependymal giant cell astrocytoma (SEGA)
associated with tuberous sclerosis (TS) who require therapeutic
intervention but are not candidates for curative surgical
resection, renal angiomyolipoma, tuberous sclerosis complex, in
combination with fulvestrant for the treatment of women with
hormone receptor (HR)-positive, human epidermal growth factor
receptor 2 (HER2)-negative advanced or metastatic breast cancer
with disease progression following endocrine therapy, as
monotherapy for the treatment of adult patients with HRpositive,
HER2-negative advanced or metastatic breast cancer with disease
progression following endocrine therapy and prior chemotherapy in
the metastatic setting, cystic fibrosis (CF) in patients age 2
years and older who have one mutation in the CFTR gene that is
responsive to ivacaftor based on clinical and/or in vitro assay
data, deleterious or suspected deleterious germline BRCA-mutated
advanced ovarian cancer in adult patients who have been treated
with three or more prior lines of chemotherapy, intermediate or
high-risk myelofibrosis, including primary myelofibrosis,
post-polycythemia vera myelofibrosis and post-essential
thrombocythemia myelofibrosis, polycythemia vera patients who have
had an inadequate response to or are intolerant of hydroxyurea, as
an adjunctive therapy to antidepressants for the treatment of major
depressive disorder (MDD), schizophrenia, cystic fibrosis (CF)
patients aged 12 years and older who are homozygous for the F508del
mutation or who have at least one mutation in the cystic fibrosis
transmembrane conductance regulator (CFTR) gene that is responsive
to tezacaftor/ivacaftor based on in vitro data and/or clinical
evidence, metastatic colorectal cancer (CRC) patients who have been
previously treated with fluoropyrimidine-, oxaliplatin- and
irinotecan-based chemotherapy, an antiVEGF therapy, and, if RAS
wild-type, an anti-EGFR therapy, locally advanced, unresectable or
metastatic gastrointestinal stromal tumor (GIST) patients who have
been previously treated with imatinib mesylate and sunitinib
malate, hepatocellular carcinoma (HCC) who have been previously
treated with sorafenib, use with sofosbuvir, with or without
ribavirin, for the treatment of chronic HCV genotype 1 or 3
infection, metastatic non-small cell lung cancer (NSCLC) patients
whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive
as detected by an FDA-approved test, opioid induced constipation
(OIC) in adult patients with chronic non-cancer pain, including
patients with chronic pain related to prior cancer or its treatment
who do not require frequent (e.g., weekly) opioid dosage
escalation, unresectable or metastatic melanoma with BRAF V600E
mutation as detected by an FDA-approved test, in combination with
trametinib, for the treatment of patients with unresectable or
metastatic melanoma with BRAF V600E or V600K mutations as detected
by an FDA-approved test, adjuvant treatment of patients with
melanoma with BRAF V600E or V600K mutations, as detected by an
FDA-approved test, and involvement of lymph node(s), following
complete resection, metastatic non-small cell lung cancer (NSCLC)
with BRAF V600E mutation as detected by an FDA-approved test,
locally advanced or metastatic anaplastic thyroid cancer (ATC) in
patients with BRAF V600E mutation and with no satisfactory
locoregional treatment options, and with or without ribavirin for
treatment of chronic HCV genotypes 1 or 4 infection in adults.
[0238] 31. The method of embodiment 30, wherein said CYP3A4
substrate drug is selected from the group consisting of lurasidone,
ranolazine, lumacaftor/ivacaftor, venetoclax, trabectedin,
ribociclib succinate, deflazacort, cinacalcet hydrochloride,
pimavanserin tartrate, aripiprazole lauroxil, cariprazine
hydrochloride, simeprevir sodium, everolimus, saxagliptin
hydrochloride, saxagliptin/metformin hydrochloride, ticagrelor,
vilazodone hydrochloride, apixaban, tofacitinib citrate, eletriptan
hydrobromide, nilotinib hydrochloride monohydrate, dronedarone
hydrochloride, fluticasone propionate/salmeterol xinafoate,
rivaroxaban, tadalafil, ibrutinib, cobimetinib, colchicine,
cabazitaxel, tolvaptan, fosaprepitant dimeglumine, aprepitant,
solifenacin succinate, erlotinib hydrochloride, ado-trastuzumab
ematansine, bosutinib monohydrate, sunitinib malate, fesoterodine
fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,
axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate,
ponatinib hydrochloride, isavuconazonium sulfate, lomitapide
mesylate, iloperidone, palbociclib, levomilnacipran hydrochloride,
pimozide, pomalidomide, abemaciclib, ivacaftor, ruxolitinib
phosphate, brexpiprazole, ivacaftor/tezacaftor, regorafenib,
daclatasvir, crizotinib, naloxegol oxalate, dabrafenib, olaparib,
elbasvir and grazoprevir.
[0239] 32. The method of embodiment 31, wherein the CYP3A4
substrate drug is lurasidone.
[0240] 33. The method of embodiment 31, wherein the CYP3A4
substrate drug is ranolazine.
[0241] 34. The method of embodiment 31, wherein the CYP3A4
substrate drug is tadalafil.
[0242] 35. The method of any of embodiments 30-34, wherein the
patient is obese.
[0243] 36. The method of embodiment 35, wherein the patient has at
least one of the following characteristics:
[0244] i) BMI of at least about 35;
[0245] ii) % IBW of at least about 150%;
[0246] iii) waist size greater than about 42 inches;
[0247] iv) % body fat greater than about 40%;
[0248] v) total body fat greater than about 40 kg; and
[0249] vi) medically diagnosed as obese.
[0250] 37. The method of any of embodiments 30-36, wherein the
CYP3A4 substrate drug is ranolazine, and the AUC of ranolazine is
maintained at a level of no more than about 150% of a normal
baseline AUC of ranolazine.
[0251] 38. The method of any of embodiments 30-36, wherein the
CYP3A4 substrate drug is ranolazine, and the C.sub.max of
ranolazine is maintained at a level of no more than about 150% of a
normal baseline C.sub.max of ranolazine.
[0252] 39. The method of any of embodiments 30-36, wherein the
CYP3A4 substrate drug is lurasidone, and the AUC of lurasidone is
maintained at a level of no more than about 216% of a normal
baseline AUC of lurasidone.
[0253] 40. The method of any of embodiments 30-36, wherein the
CYP3A4 substrate drug is lurasidone, and the C.sub.max of
lurasidone is maintained at a level of no more than about 210% of a
normal baseline C.sub.max of lurasidone.
[0254] 41. The method of any of embodiments 30-36, wherein the
CYP3A4 substrate drug is tadalafil, and the AUC of tadalafil is
maintained at a level of no more than about 410% of a normal
baseline AUC of tadalafil.
[0255] 42. The method of any of embodiments 30-36, wherein the
CYP3A4 substrate drug is tadalafil, and the a C.sub.max of
tadalafil is maintained at a level of no more than about 120% of a
normal baseline C.sub.max of tadalafil.
[0256] 43. The method of any of embodiments 30-42, wherein the
patient is a poor or intermediate CYP3A4 metabolizer.
[0257] 44. A method of treating a disease or condition in a patient
with a CYP3A4 substrate drug which is contraindicated for
concomitant use with a strong CYP3A4 inhibitor, wherein the patient
is also in need of treatment with posaconazole, comprising:
[0258] (a) treating a patient with a therapeutically effective
regimen of posaconazole to the patient;
[0259] (b) not administering the CYP3A4 substrate drug during the
administration of the posaconazole regimen;
[0260] (c) for at least about 2-21 days after stopping the
posaconazole regimen, treating the patient with, or prescribing,
the CYP3A4 substrate drug at a dose which is no more than about 50%
of the reference dose;
[0261] wherein the disease or condition treated with the CYP3A4
substrate drug is selected from the group consisting of
schizophrenia in adults and adolescents (13 to 17 years),
depressive episodes associated with Bipolar I Disorder (bipolar
depression) in adults, as monotherapy or as adjunctive therapy with
lithium or valproate, chronic angina, cystic fibrosis in patients 6
years and older who are homozygous for the F508del mutation in the
CFTR gene, chronic lymphocytic leukemia in patients with 17p
deletion, who have received at least one prior therapy,
unresectable or metastatic liposarcoma or leiomyosarcoma in
patients who received a prior anthracycline-containing regimen,
advanced or metastatic breast cancer in postmenopausal women with
hormone receptor (HR)-positive, human epidermal growth factor
receptor 2 (HER2)-negative advanced or metastatic breast cancer,
negative advanced or metastatic breast cancer in combination with
an aromatase inhibitor for postmenopausal women, Duchenne muscular
dystrophy (DMD), secondary hyperparathyroidism (HPT) in patients
with chronic kidney disease (CKD) on dialysis, hypercalcemia in
patients with parathyroid carcinoma or in patients with primary HPT
for who parathyroidectomy would be indicated on the basis of serum
calcium levels, but who are unable to undergo parathyroidectomy,
hallucinations and delusions associated with Parkinson's disease
psychosis, schizophrenia, acute manic or mixed episodes associated
with bipolar I disorder, chronic hepatitis C (CHC) infection as a
component of a combination antiviral treatment regimen with
peginterferon alfa and ribavirin in HCV genotype 1 infected
subjects with compensated liver disease, postmenopausal women with
advanced hormone receptor-positive, HER2-negative breast cancer
(advanced HR+ BC), e.g., in combination with exemestane after
failure of treatment with letrozole or anastrozole, progressive
neuroendocrine tumors of pancreatic origin (PNET), progressive,
well-differentiated, non-functional neuroendocrine tumors (NET) of
gastrointestinal (GI) or lung origin that are unresectable, locally
advanced or metastatic, advanced renal cell carcinoma (RCC), e.g.,
after failure of treatment with sunitinib or sorafenib, renal
angiomyolipoma and tuberous sclerosis complex (TSC), not requiring
immediate surgery, TSC in patients who have subependymal giant cell
astrocytoma (SEGA) that require therapeutic intervention but are
not candidates for surgical resection, type 2 diabetes mellitus in
adults as an adjunct to diet and exercise to improve glycemic
control, major depressive disorder (MDD), thrombotic cardiovascular
events (e.g., cardiovascular death, myocardial infarction, or
stroke) in patients with acute coronary syndrome (ACS), stroke and
systemic embolism in patients with nonvalvular atrial fibrillation,
deep vein thrombosis (DVT), which may lead to pulmonary embolism
(PE) in patients who have undergone hip or knee replacement
surgery, DVT, PE, recurrent DVT and PE following initial therapy,
moderate to severe active rheumatoid arthritis in patients who have
had inadequate response or tolerance to methotrexate, acute
migraine with or without aura, chronic phase and accelerated phase
Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML)
in newly diagnosed patients or in patients resistant to or
intolerant to prior therapy that included imatinib, atrial
fibrillation (AF) in patients with a history of paroxysmal or
persistant AF or atrial flutter (AFK), who are in sinus rhythm or
will be cardioverted, asthma in patients aged 4 years and older,
airflow obstruction and reducing exacerbations in patients with
chronic obstructive pulmonary disease, erectile dysfunction (ED),
benign prostatic hyperplasia (BPH), pulmonary arterial hypertension
(PAH) (WHO Group 1) to improve exercise ability, gout flares,
Familial Mediterranean fever antiretroviral therapy, anxiety
disorders, panic disorders, seizures, insomnia, hypertension,
cardiovascular disease, hyperlipidemia, cancer, such as primary
kidney cancer, advanced primary liver cancer, radioactive iodine
resistant advanced thyroid carcinoma, renal cell carcinoma,
imatinib-resistant gastrointestinal stromal tumor, mantle cell
lymphoma in patients who have received at least one prior therapy,
chronic lymphocytic leukemia/small lymphocytic lymphoma, chronic
lymphocytic leukemia/small lymphocytic lymphoma with 17p deletion,
Waldenstrom's macroglobulinemia, marginal zone lymphoma who require
systemic therapy and have received at least one prior
anti-CD20-based therapy, unresectable or metastatic melanoma with a
BRAF V600E or V600K mutation, allergies, transplantation,
hormone-refractory metastatic prostate cancer previously treated
with a docetaxel-containing treatment regimen, hormone-refractory
metastatic prostate cancer previously treated with a
docetaxel-containing treatment regimen, treatment of clinically
significant hypervolemic and euvolemic hyponatremia, including
patients with heart failure and Syndrome of Inappropriate
Antidiuretic Hormone (SIADH), prevention of acute and delayed
nausea and vomiting associated with initial and repeat courses of
highly emetogenic cancer chemotherapy (HEC) including high-dose
cisplatin, prevention of delayed nausea and vomiting associated
with initial and repeat courses of moderately emetogenic cancer
chemotherapy (MEC), over-active bladder with symptoms of urge
urinary incontinence, urgency, and urinary frequency, metastatic
non-small cell lung cancer (NSCLC) whose tumors have epidermal
growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R)
substitution mutations as detected by an FDA-approved test
receiving first-line, maintenance, or second or greater line
treatment after progression, locally advanced, unresectable or
metastatic pancreatic cancer, in combination with gemcitabine,
HER2-positive, metastatic breast cancer who previously received
trastuzumab and a taxane, separately or in combination in patients
who have either: received prior therapy for metastatic disease or
developed disease recurrence during or within six months of
completing adjuvant therapy, chronic, accelerated, or blast phase
Ph+ chronic myelogenous leukemia (CML) in adults with resistance or
intolerance to prior therapy, gastrointestinal stromal tumor (GIST)
after disease progression on or intolerance to imatinib mesylate,
advanced renal cell carcinoma (RCC), progressive,
well-differentiated pancreatic neuroendocrine tumors (pNET) in
patients with unresectable locally advanced or metastatic disease,
CCR5-tropic HIV-1 infection in patients 2 years of age and older
weighing at least 10 kg in combination with other antiretroviral
agents, advanced renal cell carcinoma, advanced soft tissue sarcoma
who have received prior chemotherapy, manic and mixed episodes
associated with Bipolar I, Major Depressive Disorder, irritability
associated with Autistic Disorder, Tourette's disorder, agitation
associated with schizophrenia or bipolar mania, advanced renal cell
carcinoma after failure of one prior systemic therapy, to improve
glycemic control in adults with type 2 diabetes mellitus (T2DM) who
have inadequate control with dapagliflozin or who are already
treated with dapagliflozin and saxagliptin, progressive, metastatic
medullary thyroid cancer (MTC), advanced renal cell carcinoma (RCC)
who have received prior anti-angiogenic therapy, chronic phase,
accelerated phase, or blast phase chronic myeloid leukemia (CML) or
Ph+ ALL in adults for whom no other tyrosine kinase inhibitor (TKI)
therapy is indicated, T315I-positive CML (chronic phase,
accelerated phase, or blast phase) or T315I-positive Philadelphia
chromosome in adults, positive acute lymphoblastic leukemia (Ph+
ALL), invasive aspergillosis, invasive mucormycosis, to reduce
low-density lipoprotein cholesterol (LDL-C), total cholesterol
(TC), apolipoprotein B (apo B), and non-high density lipoprotein
cholesterol (non-HDL-C) in patients with homozygous familial
hypercholesterolemia (HoFH), schizophrenia in adults, hormone
receptor (HR)-positive, human epidermal growth factor receptor 2
(HER2)-negative advanced or metastatic breast cancer in combination
with an aromatase inhibitor as initial endocrine based therapy in
postmenopausal women, or fulvestrant in women with disease
progression following endocrine therapy, Major Depressive Disorder
(MDD), suppression of motor and phonic tics in patients with
Tourette's Disorder who have failed to respond satisfactorily to
standard treatment, treatment of multiple myeloma in patients who
have received at least two prior therapies including lenalidomide
and a proteasome inhibitor and have demonstrated disease
progression on or within 60 days of completion of the last therapy,
non-small cell lung cancer (NSCLC) whose disease has not progressed
after four cycles of platinum-based first-line chemotherapy,
locally advanced or metastatic NSCLC after failure of at least one
prior chemotherapy regimen, locally advanced, unresectable or
metastatic pancreatic cancer, overactive bladder with symptoms of
urge urinary incontinence, urgency, and urinary frequency, advanced
renal cell carcinoma (RCC) after failure of treatment with
sunitinib or sorafenib, subependymal giant cell astrocytoma (SEGA)
associated with tuberous sclerosis (TS) who require therapeutic
intervention but are not candidates for curative surgical
resection, renal angiomyolipoma, tuberous sclerosis complex, in
combination with fulvestrant for the treatment of women with
hormone receptor (HR)-positive, human epidermal growth factor
receptor 2 (HER2)-negative advanced or metastatic breast cancer
with disease progression following endocrine therapy, as
monotherapy for the treatment of adult patients with HRpositive,
HER2-negative advanced or metastatic breast cancer with disease
progression following endocrine therapy and prior chemotherapy in
the metastatic setting, cystic fibrosis (CF) in patients age 2
years and older who have one mutation in the CFTR gene that is
responsive to ivacaftor based on clinical and/or in vitro assay
data, deleterious or suspected deleterious germline BRCA-mutated
advanced ovarian cancer in adult patients who have been treated
with three or more prior lines of chemotherapy, intermediate or
high-risk myelofibrosis, including primary myelofibrosis,
post-polycythemia vera myelofibrosis and post-essential
thrombocythemia myelofibrosis, polycythemia vera patients who have
had an inadequate response to or are intolerant of hydroxyurea, as
an adjunctive therapy to antidepressants for the treatment of major
depressive disorder (MDD), schizophrenia, cystic fibrosis (CF)
patients aged 12 years and older who are homozygous for the F508del
mutation or who have at least one mutation in the cystic fibrosis
transmembrane conductance regulator (CFTR) gene that is responsive
to tezacaftor/ivacaftor based on in vitro data and/or clinical
evidence, metastatic colorectal cancer (CRC) patients who have been
previously treated with fluoropyrimidine-, oxaliplatin- and
irinotecan-based chemotherapy, an antiVEGF therapy, and, if RAS
wild-type, an anti-EGFR therapy, locally advanced, unresectable or
metastatic gastrointestinal stromal tumor (GIST) patients who have
been previously treated with imatinib mesylate and sunitinib
malate, hepatocellular carcinoma (HCC) who have been previously
treated with sorafenib, use with sofosbuvir, with or without
ribavirin, for the treatment of chronic HCV genotype 1 or 3
infection, metastatic non-small cell lung cancer (NSCLC) patients
whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive
as detected by an FDA-approved test, opioid induced constipation
(OIC) in adult patients with chronic non-cancer pain, including
patients with chronic pain related to prior cancer or its treatment
who do not require frequent (e.g., weekly) opioid dosage
escalation, unresectable or metastatic melanoma with BRAF V600E
mutation as detected by an FDA-approved test, in combination with
trametinib, for the treatment of patients with unresectable or
metastatic melanoma with BRAF V600E or V600K mutations as detected
by an FDA-approved test, adjuvant treatment of patients with
melanoma with BRAF V600E or V600K mutations, as detected by an
FDA-approved test, and involvement of lymph node(s), following
complete resection, metastatic non-small cell lung cancer (NSCLC)
with BRAF V600E mutation as detected by an FDA-approved test,
locally advanced or metastatic anaplastic thyroid cancer (ATC) in
patients with BRAF V600E mutation and with no satisfactory
locoregional treatment options, and with or without ribavirin for
treatment of chronic HCV genotypes 1 or 4 infection in adults.
[0262] 45. The method of embodiment 44, wherein said CYP3A4
substrate drug is selected from the group consisting of lurasidone,
ranolazine, lumacaftor/ivacaftor, venetoclax, trabectedin,
ribociclib succinate, deflazacort, cinacalcet hydrochloride,
pimavanserin tartrate, aripiprazole lauroxil, cariprazine
hydrochloride, simeprevir sodium, everolimus, saxagliptin
hydrochloride, saxagliptin/metformin hydrochloride, ticagrelor,
vilazodone hydrochloride, apixaban, tofacitinib citrate, eletriptan
hydrobromide, nilotinib hydrochloride monohydrate, dronedarone
hydrochloride, fluticasone propionate/salmeterol xinafoate,
rivaroxaban, tadalafil, ibrutinib, cobimetinib, colchicine,
cabazitaxel, tolvaptan, fosaprepitant dimeglumine, aprepitant,
solifenacin succinate, erlotinib hydrochloride, ado-trastuzumab
ematansine, bosutinib monohydrate, sunitinib malate, fesoterodine
fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,
axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate,
ponatinib hydrochloride, isavuconazonium sulfate, lomitapide
mesylate, iloperidone, palbociclib, levomilnacipran hydrochloride,
pimozide, pomalidomide, abemaciclib, ivacaftor, ruxolitinib
phosphate, brexpiprazole, ivacaftor/tezacaftor, regorafenib,
daclatasvir, crizotinib, naloxegol oxalate, dabrafenib, olaparib,
elbasvir and grazoprevir.
[0263] 46. The method of embodiment 45, wherein the CYP3A4
substrate drug is lurasidone.
[0264] 47. The method of embodiment 45, wherein the CYP3A4
substrate drug is ranolazine.
[0265] 48. The method of embodiment 45, wherein the CYP3A4
substrate drug is tadalafil.
[0266] 49. The method of any of embodiments 44-48, wherein the
patient is obese.
[0267] 50. The method of embodiment 49, wherein the patient has at
least one of the following characteristics:
[0268] i) BMI of at least about 35;
[0269] ii) % IBW of at least about 150%;
[0270] iii) waist size greater than about 42 inches;
[0271] iv) % body fat greater than about 40%;
[0272] v) total body fat greater than about 40 kg; and
[0273] vi) medically diagnosed as obese.
[0274] 51. The method of any of embodiments 44-50, wherein the
CYP3A4 substrate drug is ranolazine, and the AUC of ranolazine is
maintained at a level of no more than about a normal baseline AUC
of ranolazine to about 150% of the normal baseline AUC of
ranolazine.
[0275] 52. The method of any of embodiments 44-50, wherein the
CYP3A4 substrate drug is ranolazine, and the C.sub.max of
ranolazine is maintained at a level of no more than about a normal
baseline C.sub.max of ranolazine to about 150% of the normal
baseline C.sub.max of ranolazine.
[0276] 53. The method of any of embodiments 44-50, wherein the
CYP3A4 substrate drug is lurasidone, and the AUC of lurasidone is
maintained at a level of no more than about a normal baseline AUC
of lurasidone to about 216% of the normal baseline AUC of
lurasidone.
[0277] 54. The method of any of embodiments 44-50, wherein the
CYP3A4 substrate drug is lurasidone, and the C.sub.max of
lurasidone is maintained at a level of no more than about a normal
baseline C.sub.max of lurasidone to about 210% of the normal
baseline C.sub.max of lurasidone.
[0278] 55. The method of any of embodiments 44-50, wherein the
CYP3A4 substrate drug is tadalafil, and the AUC of tadalafil is
maintained at a level of no more than about 410% of a normal
baseline AUC of tadalafil.
[0279] 56. The method of any of embodiments 44-50, wherein the
CYP3A4 substrate drug is tadalafil, and the a C.sub.max of
tadalafil is maintained at a level of no more than about 120% of a
normal baseline C.sub.max of tadalafil.
[0280] 57. The method of embodiments 44-56, wherein the patient is
a poor or intermediate CYP3A4 metabolizer.
[0281] 58. The method of embodiment 44, wherein the CYP3A4
substrate drug is ranolazine and the daily dose is no more than
about 500 mg for at least about 2-21 days after discontinuation of
the posaconazole regimen.
[0282] 59. A method of treating a patient in need thereof
comprising delaying a first treatment of a CYP3A4 substrate drug
until about 2-21 days after stopping administration of
posaconazole.
[0283] 60. The method of embodiment 59, wherein said CYP3A4
substrate drug is selected from the group consisting of lurasidone,
ranolazine, lumacaftor/ivacaftor, venetoclax, trabectedin,
ribociclib succinate, deflazacort, cinacalcet hydrochloride,
pimavanserin tartrate, aripiprazole lauroxil, cariprazine
hydrochloride, simeprevir sodium, everolimus, saxagliptin
hydrochloride, saxagliptin/metformin hydrochloride, ticagrelor,
vilazodone hydrochloride, apixaban, tofacitinib citrate, eletriptan
hydrobromide, nilotinib hydrochloride monohydrate, dronedarone
hydrochloride, fluticasone propionate/salmeterol xinafoate,
rivaroxaban, tadalafil, ibrutinib, cobimetinib, colchicine,
cabazitaxel, tolvaptan, fosaprepitant dimeglumine, aprepitant,
solifenacin succinate, erlotinib hydrochloride, ado-trastuzumab
ematansine, bosutinib monohydrate, sunitinib malate, fesoterodine
fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,
axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate,
ponatinib hydrochloride, isavuconazonium sulfate, lomitapide
mesylate, iloperidone, palbociclib, levomilnacipran hydrochloride,
pimozide, pomalidomide, abemaciclib, ivacaftor, ruxolitinib
phosphate, brexpiprazole, ivacaftor/tezacaftor, regorafenib,
daclatasvir, crizotinib, naloxegol oxalate, dabrafenib, olaparib,
and elbasvir and grazoprevir.
[0284] 61. The method of embodiment 60, wherein the CYP3A4
substrate drug is lurasidone.
[0285] 62. The method of embodiment 60, wherein the CYP3A4
substrate drug is ranolazine.
[0286] 63. The method of embodiment 60, wherein the CYP3A4
substrate drug is tadalafil.
[0287] 64. The method of any of embodiments 59-63, wherein the
patient is obese.
[0288] 65. The method of embodiment 64, wherein the patient has at
least one of the following characteristics:
[0289] i) BMI of at least about 35;
[0290] ii) % IBW of at least about 150%;
[0291] iii) waist size greater than about 42 inches;
[0292] iv) % body fat greater than about 40%;
[0293] v) total body fat greater than about 40 kg; and
[0294] vi) medically diagnosed as obese.
[0295] 66. The method of any of embodiments 59-65, wherein the
CYP3A4 substrate drug is ranolazine, and the AUC of ranolazine is
maintained at a level of no more than about 150% of a normal
baseline AUC of ranolazine.
[0296] 67. The method of any of embodiments 59-65, wherein the
CYP3A4 substrate drug is ranolazine, and the C.sub.max of
ranolazine is maintained at a level of no more than about 150% of a
normal baseline C.sub.max of ranolazine.
[0297] 68. The method of any of embodiments 59-65, wherein the
CYP3A4 substrate drug is lurasidone, and the AUC of lurasidone is
maintained at a level of no more than about 216% of a normal
baseline AUC of lurasidone.
[0298] 68. The method of any of embodiments 59-65, wherein the
CYP3A4 substrate drug is lurasidone, and the C.sub.max of
lurasidone is maintained at a level of no more than about 210% of a
normal baseline C.sub.max of lurasidone.
[0299] 69. The method of any of embodiments 59-65, wherein the
CYP3A4 substrate drug is tadalafil, and the AUC of tadalafil is
maintained at a level of no more than about 410% of a normal
baseline AUC of tadalafil.
[0300] 70. The method of any of embodiments 59-65, wherein the
CYP3A4 substrate drug is tadalafil, and the a C.sub.max of
tadalafil is maintained at a level of no more than about 120% of a
normal baseline C.sub.max of tadalafil.
[0301] 80. The method of embodiments 59-70, wherein the patient is
a poor or intermediate CYP3A4 metabolizer.
[0302] 81. A method of treating a patient previously on
posaconazole with a CYP3A4 substrate drug which is contraindicated
for concomitant use with a strong CYP3A4 inhibitor comprising,
delaying a first treatment, or prescribing a first treatment to be
delayed, of the CYP3A4 substrate drug for at least about 2-21 days
after posaconazole administration has ceased.
[0303] 82. The method of embodiment 81, wherein said CYP3A4
substrate drug is selected from the group consisting of lurasidone,
ranolazine, lumacaftor/ivacaftor, venetoclax, trabectedin,
ribociclib succinate, deflazacort, cinacalcet hydrochloride,
pimavanserin tartrate, aripiprazole lauroxil, cariprazine
hydrochloride, simeprevir sodium, everolimus, saxagliptin
hydrochloride, saxagliptin/metformin hydrochloride, ticagrelor,
vilazodone hydrochloride, apixaban, tofacitinib citrate, eletriptan
hydrobromide, nilotinib hydrochloride monohydrate, dronedarone
hydrochloride, fluticasone propionate/salmeterol xinafoate,
rivaroxaban, tadalafil, ibrutinib, cobimetinib, colchicine,
cabazitaxel, tolvaptan, fosaprepitant dimeglumine, aprepitant,
solifenacin succinate, erlotinib hydrochloride, ado-trastuzumab
ematansine, bosutinib monohydrate, sunitinib malate, fesoterodine
fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,
axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate,
ponatinib hydrochloride, isavuconazonium sulfate, lomitapide
mesylate, iloperidone, palbociclib, levomilnacipran hydrochloride,
pimozide, pomalidomide, abemaciclib, ivacaftor, ruxolitinib
phosphate, brexpiprazole, ivacaftor/tezacaftor, regorafenib,
daclatasvir, crizotinib, naloxegol oxalate, dabrafenib, olaparib,
and elbasvir and grazoprevir.
[0304] 83. The method of embodiment 82, wherein the CYP3A4
substrate drug is lurasidone.
[0305] 84. The method of embodiment 82, wherein the CYP3A4
substrate drug is ranolazine.
[0306] 85. The method of embodiment 45, wherein the CYP3A4
substrate drug is tadalafil.
[0307] 86. The method of any of embodiments 81-85, wherein the
patient is obese.
[0308] 87. The method of embodiment 86, wherein the patient has at
least one of the following characteristics:
[0309] i) BMI of at least about 35;
[0310] ii) % IBW of at least about 150%;
[0311] iii) waist size greater than about 42 inches;
[0312] iv) % body fat greater than about 40%;
[0313] v) total body fat greater than about 40 kg; and
[0314] vi) medically diagnosed as obese.
[0315] 88. The method of any of embodiments 81-87, wherein the
CYP3A4 substrate drug is ranolazine, and the AUC of ranolazine is
maintained at a level of no more than about 150% of a normal
baseline AUC of ranolazine.
[0316] 89. The method of any of embodiments 81-87, wherein the
CYP3A4 substrate drug is ranolazine, and the C.sub.max of
ranolazine is maintained at a level of no more than about 150% of a
normal baseline C.sub.max of ranolazine.
[0317] 90. The method of any of embodiments 81-87, wherein the
CYP3A4 substrate drug is lurasidone, and the AUC of lurasidone is
maintained at a level of no more than about 216% of a normal
baseline AUC of lurasidone.
[0318] 91. The method of any of embodiments 81-87, wherein the
CYP3A4 substrate drug is lurasidone, and the C.sub.max of
lurasidone is maintained at a level of no more than about 210% of a
normal baseline C.sub.max of lurasidone.
[0319] 92. The method of any of embodiments 81-87, wherein the
CYP3A4 substrate drug is tadalafil, and the AUC of tadalafil is
maintained at a level of no more than about 410% of a normal
baseline AUC of tadalafil.
[0320] 93. The method of any of embodiments 81-87, wherein the
CYP3A4 substrate drug is tadalafil, and the a C.sub.max of
tadalafil is maintained at a level of no more than about 120% of a
normal baseline C.sub.max of tadalafil.
[0321] 94. The method of embodiments 81-93, wherein the patient is
a poor or intermediate CYP3A4 metabolizer.
[0322] 95. A method of treating a patient with a CYP3A4 substrate
drug contraindicated for concomitant use with a strong CYP3A4
inhibitor, comprising treating the patient, or prescribing a
treatment of, the CYP3A4 substrate drug at a dose which is less
than or equal to about 50% of the reference dose for a period of at
least about 2-21 days after stopping administration of
posaconazole.
[0323] 96. The method of embodiment 95, wherein said CYP3A4
substrate drug is selected from the group consisting of lurasidone,
ranolazine, lumacaftor/ivacaftor, venetoclax, trabectedin,
ribociclib succinate, deflazacort, cinacalcet hydrochloride,
pimavanserin tartrate, aripiprazole lauroxil, cariprazine
hydrochloride, simeprevir sodium, everolimus, saxagliptin
hydrochloride, saxagliptin/metformin hydrochloride, ticagrelor,
vilazodone hydrochloride, apixaban, tofacitinib citrate, eletriptan
hydrobromide, nilotinib hydrochloride monohydrate, dronedarone
hydrochloride, fluticasone propionate/salmeterol xinafoate,
rivaroxaban, tadalafil, ibrutinib, cobimetinib, colchicine,
cabazitaxel, tolvaptan, fosaprepitant dimeglumine, aprepitant,
solifenacin succinate, erlotinib hydrochloride, ado-trastuzumab
ematansine, bosutinib monohydrate, sunitinib malate, fesoterodine
fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,
axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate,
ponatinib hydrochloride, isavuconazonium sulfate, lomitapide
mesylate, iloperidone, palbociclib, levomilnacipran hydrochloride,
pimozide, pomalidomide, abemaciclib, ivacaftor, ruxolitinib
phosphate, brexpiprazole, ivacaftor/tezacaftor, regorafenib,
daclatasvir, crizotinib, naloxegol oxalate, dabrafenib, olaparib,
and elbasvir and grazoprevir.
[0324] 97. The method of embodiment 96, wherein the CYP3A4
substrate drug is lurasidone.
[0325] 98. The method of embodiment 96, wherein the CYP3A4
substrate drug is ranolazine.
[0326] 99. The method of embodiment 96, wherein the CYP3A4
substrate drug is tadalafil.
[0327] 100. The method of any of embodiments 95-99, wherein the
patient is obese.
[0328] 101. The method of embodiment 100, wherein the patient has
at least one of the following characteristics:
[0329] i) BMI of at least about 35;
[0330] ii) % IBW of at least about 150%;
[0331] iii) waist size greater than about 42 inches;
[0332] iv) % body fat greater than about 40%;
[0333] v) total body fat greater than about 40 kg; and
[0334] vi) medically diagnosed as obese.
[0335] 102. The method of any of embodiments 95-101, wherein the
CYP3A4 substrate drug is ranolazine, and the AUC of ranolazine is
maintained at a level of no more than about a normal baseline AUC
of ranolazine to about 150% of the normal baseline AUC of
ranolazine.
[0336] 103. The method of any of embodiments 95-101, wherein the
CYP3A4 substrate drug is ranolazine, and the C.sub.max of
ranolazine is maintained at a level of no more than about a normal
baseline C.sub.max of ranolazine to about 150% of the normal
baseline C.sub.max of ranolazine.
[0337] 104. The method of any of embodiments 95-101, wherein the
CYP3A4 substrate drug is lurasidone, and the AUC of lurasidone is
maintained at a level of no more than about a normal baseline AUC
of lurasidone to about 216% of the normal baseline AUC of
lurasidone.
[0338] 105. The method of any of embodiments 95-101, wherein the
CYP3A4 substrate drug is lurasidone, and the C.sub.max of
lurasidone is maintained at a level of no more than about a normal
baseline C.sub.max of lurasidone to about 210% of the normal
baseline C.sub.max of lurasidone.
[0339] 106. The method of any of embodiments 95-101, wherein the
CYP3A4 substrate drug is tadalafil, and the AUC of tadalafil is
maintained at a level of no more than about 410% of a normal
baseline AUC of tadalafil.
[0340] 107. The method of any of embodiments 95-101, wherein the
CYP3A4 substrate drug is tadalafil, and the a C.sub.max of
tadalafil is maintained at a level of no more than about 120% of a
normal baseline C.sub.max of tadalafil.
[0341] 108. The method of embodiments 95-107, wherein the patient
is a poor or intermediate CYP3A4 metabolizer.
[0342] 109. The method of embodiment 95, wherein the CYP3A4
substrate drug is ranolazine and the daily dose is no more than
about 500 mg for at least about 2-21 days after discontinuation of
the posaconazole regimen.
[0343] 110. A method of treating a disease or condition in a
patient with a CYP3A4 substrate drug which is contraindicated for
concomitant use with a strong CYP3A4 inhibitor, comprising:
[0344] (a) delaying a first treatment, or prescribing a delay of
the first treatment, of the CYP3A4 substrate drug for at least 2-21
days after stopping administration of posaconazole; and then
[0345] (b) administering the CYP3A4 substrate drug;
[0346] wherein the disease or condition treated with the CYP3A4
substrate drug is selected from the group consisting of
schizophrenia in adults and adolescents (13 to 17 years),
depressive episodes associated with Bipolar I Disorder (bipolar
depression) in adults, as monotherapy or as adjunctive therapy with
lithium or valproate, chronic angina, cystic fibrosis in patients 6
years and older who are homozygous for the F508del mutation in the
CFTR gene, chronic lymphocytic leukemia in patients with 17p
deletion, who have received at least one prior therapy,
unresectable or metastatic liposarcoma or leiomyosarcoma in
patients who received a prior anthracycline-containing regimen,
advanced or metastatic breast cancer in postmenopausal women with
hormone receptor (HR)-positive, human epidermal growth factor
receptor 2 (HER2)-negative advanced or metastatic breast cancer,
negative advanced or metastatic breast cancer in combination with
an aromatase inhibitor for postmenopausal women, Duchenne muscular
dystrophy (DMD), secondary hyperparathyroidism (HPT) in patients
with chronic kidney disease (CKD) on dialysis, hypercalcemia in
patients with parathyroid carcinoma or in patients with primary HPT
for who parathyroidectomy would be indicated on the basis of serum
calcium levels, but who are unable to undergo parathyroidectomy,
hallucinations and delusions associated with Parkinson's disease
psychosis, schizophrenia, acute manic or mixed episodes associated
with bipolar I disorder, chronic hepatitis C (CHC) infection as a
component of a combination antiviral treatment regimen with
peginterferon alfa and ribavirin in HCV genotype 1 infected
subjects with compensated liver disease, postmenopausal women with
advanced hormone receptor-positive, HER2-negative breast cancer
(advanced HR+ BC), e.g., in combination with exemestane after
failure of treatment with letrozole or anastrozole, progressive
neuroendocrine tumors of pancreatic origin (PNET), progressive,
well-differentiated, non-functional neuroendocrine tumors (NET) of
gastrointestinal (GI) or lung origin that are unresectable, locally
advanced or metastatic, advanced renal cell carcinoma (RCC), e.g.,
after failure of treatment with sunitinib or sorafenib, renal
angiomyolipoma and tuberous sclerosis complex (TSC), not requiring
immediate surgery, TSC in patients who have subependymal giant cell
astrocytoma (SEGA) that require therapeutic intervention but are
not candidates for surgical resection, type 2 diabetes mellitus in
adults as an adjunct to diet and exercise to improve glycemic
control, major depressive disorder (MDD), thrombotic cardiovascular
events (e.g., cardiovascular death, myocardial infarction, or
stroke) in patients with acute coronary syndrome (ACS), stroke and
systemic embolism in patients with nonvalvular atrial fibrillation,
deep vein thrombosis (DVT), which may lead to pulmonary embolism
(PE) in patients who have undergone hip or knee replacement
surgery, DVT, PE, recurrent DVT and PE following initial therapy,
moderate to severe active rheumatoid arthritis in patients who have
had inadequate response or tolerance to methotrexate, acute
migraine with or without aura, chronic phase and accelerated phase
Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML)
in newly diagnosed patients or in patients resistant to or
intolerant to prior therapy that included imatinib, atrial
fibrillation (AF) in patients with a history of paroxysmal or
persistant AF or atrial flutter (AFK), who are in sinus rhythm or
will be cardioverted, asthma in patients aged 4 years and older,
airflow obstruction and reducing exacerbations in patients with
chronic obstructive pulmonary disease, erectile dysfunction (ED),
benign prostatic hyperplasia (BPH), pulmonary arterial hypertension
(PAH) (WHO Group 1) to improve exercise ability, gout flares,
Familial Mediterranean fever, antiretroviral therapy, anxiety
disorders, panic disorders, seizures, insomnia, hypertension,
cardiovascular disease, hyperlipidemia, cancer, such as primary
kidney cancer, advanced primary liver cancer, radioactive iodine
resistant advanced thyroid carcinoma, renal cell carcinoma,
imatinib-resistant gastrointestinal stromal tumor, mantle cell
lymphoma in patients who have received at least one prior therapy,
chronic lymphocytic leukemia/small lymphocytic lymphoma, chronic
lymphocytic leukemia/small lymphocytic lymphoma with 17p deletion,
Waldenstrom's macroglobulinemia, marginal zone lymphoma who require
systemic therapy and have received at least one prior
anti-CD20-based therapy, unresectable or metastatic melanoma with a
BRAF V600E or V600K mutation, allergies, transplantation,
hormone-refractory metastatic prostate cancer previously treated
with a docetaxel-containing treatment regimen, hormone-refractory
metastatic prostate cancer previously treated with a
docetaxel-containing treatment regimen, treatment of clinically
significant hypervolemic and euvolemic hyponatremia, including
patients with heart failure and Syndrome of Inappropriate
Antidiuretic Hormone (SIADH), prevention of acute and delayed
nausea and vomiting associated with initial and repeat courses of
highly emetogenic cancer chemotherapy (HEC) including high-dose
cisplatin, prevention of delayed nausea and vomiting associated
with initial and repeat courses of moderately emetogenic cancer
chemotherapy (MEC), over-active bladder with symptoms of urge
urinary incontinence, urgency, and urinary frequency, metastatic
non-small cell lung cancer (NSCLC) whose tumors have epidermal
growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R)
substitution mutations as detected by an FDA-approved test
receiving first-line, maintenance, or second or greater line
treatment after progression, locally advanced, unresectable or
metastatic pancreatic cancer, in combination with gemcitabine,
HER2-positive, metastatic breast cancer who previously received
trastuzumab and a taxane, separately or in combination in patients
who have either: received prior therapy for metastatic disease or
developed disease recurrence during or within six months of
completing adjuvant therapy, chronic, accelerated, or blast phase
Ph+ chronic myelogenous leukemia (CML) in adults with resistance or
intolerance to prior therapy, gastrointestinal stromal tumor (GIST)
after disease progression on or intolerance to imatinib mesylate,
advanced renal cell carcinoma (RCC), progressive,
well-differentiated pancreatic neuroendocrine tumors (pNET) in
patients with unresectable locally advanced or metastatic disease,
CCR5-tropic HIV-1 infection in patients 2 years of age and older
weighing at least 10 kg in combination with other antiretroviral
agents, advanced renal cell carcinoma, advanced soft tissue sarcoma
who have received prior chemotherapy, manic and mixed episodes
associated with Bipolar I, Major Depressive Disorder, irritability
associated with Autistic Disorder, Tourette's disorder, agitation
associated with schizophrenia or bipolar mania, advanced renal cell
carcinoma after failure of one prior systemic therapy, to improve
glycemic control in adults with type 2 diabetes mellitus (T2DM) who
have inadequate control with dapagliflozin or who are already
treated with dapagliflozin and saxagliptin, progressive, metastatic
medullary thyroid cancer (MTC), advanced renal cell carcinoma (RCC)
who have received prior anti-angiogenic therapy, chronic phase,
accelerated phase, or blast phase chronic myeloid leukemia (CML) or
Ph+ ALL in adults for whom no other tyrosine kinase inhibitor (TKI)
therapy is indicated, T315I-positive CML (chronic phase,
accelerated phase, or blast phase) or T315I-positive Philadelphia
chromosome in adults, positive acute lymphoblastic leukemia (Ph+
ALL), invasive aspergillosis, invasive mucormycosis, to reduce
low-density lipoprotein cholesterol (LDL-C), total cholesterol
(TC), apolipoprotein B (apo B), and non-high density lipoprotein
cholesterol (non-HDL-C) in patients with homozygous familial
hypercholesterolemia (HoFH), schizophrenia in adults, hormone
receptor (HR)-positive, human epidermal growth factor receptor 2
(HER2)-negative advanced or metastatic breast cancer in combination
with an aromatase inhibitor as initial endocrine based therapy in
postmenopausal women, or fulvestrant in women with disease
progression following endocrine therapy, Major Depressive Disorder
(MDD), suppression of motor and phonic tics in patients with
Tourette's Disorder who have failed to respond satisfactorily to
standard treatment, treatment of multiple myeloma in patients who
have received at least two prior therapies including lenalidomide
and a proteasome inhibitor and have demonstrated disease
progression on or within 60 days of completion of the last therapy,
non-small cell lung cancer (NSCLC) whose disease has not progressed
after four cycles of platinum-based first-line chemotherapy,
locally advanced or metastatic NSCLC after failure of at least one
prior chemotherapy regimen, locally advanced, unresectable or
metastatic pancreatic cancer, overactive bladder with symptoms of
urge urinary incontinence, urgency, and urinary frequency, advanced
renal cell carcinoma (RCC) after failure of treatment with
sunitinib or sorafenib, subependymal giant cell astrocytoma (SEGA)
associated with tuberous sclerosis (TS) who require therapeutic
intervention but are not candidates for curative surgical
resection, renal angiomyolipoma, tuberous sclerosis complex, in
combination with fulvestrant for the treatment of women with
hormone receptor (HR)-positive, human epidermal growth factor
receptor 2 (HER2)-negative advanced or metastatic breast cancer
with disease progression following endocrine therapy, as
monotherapy for the treatment of adult patients with HRpositive,
HER2-negative advanced or metastatic breast cancer with disease
progression following endocrine therapy and prior chemotherapy in
the metastatic setting, cystic fibrosis (CF) in patients age 2
years and older who have one mutation in the CFTR gene that is
responsive to ivacaftor based on clinical and/or in vitro assay
data, deleterious or suspected deleterious germline BRCA-mutated
advanced ovarian cancer in adult patients who have been treated
with three or more prior lines of chemotherapy, intermediate or
high-risk myelofibrosis, including primary myelofibrosis,
post-polycythemia vera myelofibrosis and post-essential
thrombocythemia myelofibrosis, polycythemia vera patients who have
had an inadequate response to or are intolerant of hydroxyurea, as
an adjunctive therapy to antidepressants for the treatment of major
depressive disorder (MDD), schizophrenia, cystic fibrosis (CF)
patients aged 12 years and older who are homozygous for the F508del
mutation or who have at least one mutation in the cystic fibrosis
transmembrane conductance regulator (CFTR) gene that is responsive
to tezacaftor/ivacaftor based on in vitro data and/or clinical
evidence, metastatic colorectal cancer (CRC) patients who have been
previously treated with fluoropyrimidine-, oxaliplatin- and
irinotecan-based chemotherapy, an antiVEGF therapy, and, if RAS
wild-type, an anti-EGFR therapy, locally advanced, unresectable or
metastatic gastrointestinal stromal tumor (GIST) patients who have
been previously treated with imatinib mesylate and sunitinib
malate, hepatocellular carcinoma (HCC) who have been previously
treated with sorafenib, use with sofosbuvir, with or without
ribavirin, for the treatment of chronic HCV genotype 1 or 3
infection, metastatic non-small cell lung cancer (NSCLC) patients
whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive
as detected by an FDA-approved test, opioid induced constipation
(OIC) in adult patients with chronic non-cancer pain, including
patients with chronic pain related to prior cancer or its treatment
who do not require frequent (e.g., weekly) opioid dosage
escalation, unresectable or metastatic melanoma with BRAF V600E
mutation as detected by an FDA-approved test, in combination with
trametinib, for the treatment of patients with unresectable or
metastatic melanoma with BRAF V600E or V600K mutations as detected
by an FDA-approved test, adjuvant treatment of patients with
melanoma with BRAF V600E or V600K mutations, as detected by an
FDA-approved test, and involvement of lymph node(s), following
complete resection, metastatic non-small cell lung cancer (NSCLC)
with BRAF V600E mutation as detected by an FDA-approved test,
locally advanced or metastatic anaplastic thyroid cancer (ATC) in
patients with BRAF V600E mutation and with no satisfactory
locoregional treatment options, and with or without ribavirin for
treatment of chronic HCV genotypes 1 or 4 infection in adults.
[0347] 111. The method of embodiment 110, wherein said CYP3A4
substrate drug is selected from the group consisting of lurasidone,
ranolazine, lumacaftor/ivacaftor, venetoclax, trabectedin,
ribociclib succinate, deflazacort, cinacalcet hydrochloride,
pimavanserin tartrate, aripiprazole lauroxil, cariprazine
hydrochloride, simeprevir sodium, everolimus, saxagliptin
hydrochloride, saxagliptin/metformin hydrochloride, ticagrelor,
vilazodone hydrochloride, apixaban, tofacitinib citrate, eletriptan
hydrobromide, nilotinib hydrochloride monohydrate, dronedarone
hydrochloride, fluticasone propionate/salmeterol xinafoate,
rivaroxaban, tadalafil, ibrutinib, cobimetinib, colchicine,
cabazitaxel, tolvaptan, fosaprepitant dimeglumine, aprepitant,
solifenacin succinate, erlotinib hydrochloride, ado-trastuzumab
ematansine, bosutinib monohydrate, sunitinib malate, fesoterodine
fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,
axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate,
ponatinib hydrochloride, isavuconazonium sulfate, lomitapide
mesylate, iloperidone, palbociclib, levomilnacipran hydrochloride,
pimozide, pomalidomide, abemaciclib, ivacaftor, ruxolitinib
phosphate, brexpiprazole, ivacaftor/tezacaftor, regorafenib,
daclatasvir, crizotinib, naloxegol oxalate, dabrafenib, olaparib,
and elbasvir and grazoprevir.
[0348] 112. The method of embodiment 111, wherein the CYP3A4
substrate drug is lurasidone.
[0349] 113. The method of embodiment 111, wherein the CYP3A4
substrate drug is ranolazine.
[0350] 114. The method of embodiment 111, wherein the CYP3A4
substrate drug is tadalafil.
[0351] 115. The method of any of embodiments 110-114, wherein the
patient is obese.
[0352] 116. The method of embodiment 115, wherein the patient has
at least one of the following characteristics:
[0353] i) BMI of at least about 35;
[0354] ii) % IBW of at least about 150%;
[0355] iii) waist size greater than about 42 inches;
[0356] iv) % body fat greater than about 40%;
[0357] v) total body fat greater than about 40 kg; and
[0358] vi) medically diagnosed as obese.
[0359] 117. The method of any of embodiments 110-116, wherein the
CYP3A4 substrate drug is ranolazine, and the AUC of ranolazine is
maintained at a level of no more than about 150% of a normal
baseline AUC of ranolazine.
[0360] 118. The method of any of embodiments 110-116, wherein the
CYP3A4 substrate drug is ranolazine, and the C.sub.max of
ranolazine is maintained at a level of no more than about 150% of a
normal baseline C.sub.max of ranolazine.
[0361] 119. The method of any of embodiments 110-116, wherein the
CYP3A4 substrate drug is lurasidone, and the AUC of lurasidone is
maintained at a level of no more than about 216% of a normal
baseline AUC of lurasidone.
[0362] 120. The method of any of embodiments 110-116, wherein the
CYP3A4 substrate drug is lurasidone, and the C.sub.max of
lurasidone is maintained at a level of no more than about 210% of a
normal baseline C.sub.max of lurasidone.
[0363] 121. The method of any of embodiments 110-116, wherein the
CYP3A4 substrate drug is tadalafil, and the AUC of tadalafil is
maintained at a level of no more than about 410% of a normal
baseline AUC of tadalafil.
[0364] 122. The method of any of embodiments 110-116, wherein the
CYP3A4 substrate drug is tadalafil, and the a C.sub.max of
tadalafil is maintained at a level of no more than about 120% of a
normal baseline C.sub.max of tadalafil.
[0365] 123. The method of embodiments 110-122, wherein the patient
is a poor or intermediate CYP3A4 metabolizer.
[0366] 124. A method of treating a patient with a CYP3A4 substrate
drug which is contraindicated for concomitant use with a strong
CYP3A4 inhibitor, comprising:
[0367] (a) delaying a first treatment, or prescribing a delay in
the first treatment, of the CYP3A4 substrate drug for at least
about 2-21 days after stopping administration of the posaconazole
regimen; and then
(d) treating the patient with the CYP3A4 substrate drug at a dose
which is less than or equal to about 50% of the reference dose for
at least about 2-21 days after stopping administration of the
posaconazole regimen;
[0368] wherein the disease or condition treated with the CYP3A4
substrate drug is selected from the group consisting of
schizophrenia in adults and adolescents (13 to 17 years),
depressive episodes associated with Bipolar I Disorder (bipolar
depression) in adults, as monotherapy or as adjunctive therapy with
lithium or valproate, chronic angina, cystic fibrosis in patients 6
years and older who are homozygous for the F508del mutation in the
CFTR gene, chronic lymphocytic leukemia in patients with 17p
deletion, who have received at least one prior therapy,
unresectable or metastatic liposarcoma or leiomyosarcoma in
patients who received a prior anthracycline-containing regimen,
advanced or metastatic breast cancer in postmenopausal women with
hormone receptor (HR)-positive, human epidermal growth factor
receptor 2 (HER2)-negative advanced or metastatic breast cancer,
negative advanced or metastatic breast cancer in combination with
an aromatase inhibitor for postmenopausal women, Duchenne muscular
dystrophy (DMD), secondary hyperparathyroidism (HPT) in patients
with chronic kidney disease (CKD) on dialysis, hypercalcemia in
patients with parathyroid carcinoma or in patients with primary HPT
for who parathyroidectomy would be indicated on the basis of serum
calcium levels, but who are unable to undergo parathyroidectomy,
hallucinations and delusions associated with Parkinson's disease
psychosis, schizophrenia, acute manic or mixed episodes associated
with bipolar I disorder, chronic hepatitis C (CHC) infection as a
component of a combination antiviral treatment regimen with
peginterferon alfa and ribavirin in HCV genotype 1 infected
subjects with compensated liver disease, postmenopausal women with
advanced hormone receptor-positive, HER2-negative breast cancer
(advanced HR+ BC), e.g., in combination with exemestane after
failure of treatment with letrozole or anastrozole, progressive
neuroendocrine tumors of pancreatic origin (PNET), progressive,
well-differentiated, non-functional neuroendocrine tumors (NET) of
gastrointestinal (GI) or lung origin that are unresectable, locally
advanced or metastatic, advanced renal cell carcinoma (RCC), e.g.,
after failure of treatment with sunitinib or sorafenib, renal
angiomyolipoma and tuberous sclerosis complex (TSC), not requiring
immediate surgery, TSC in patients who have subependymal giant cell
astrocytoma (SEGA) that require therapeutic intervention but are
not candidates for surgical resection, type 2 diabetes mellitus in
adults as an adjunct to diet and exercise to improve glycemic
control, major depressive disorder (MDD), thrombotic cardiovascular
events (e.g., cardiovascular death, myocardial infarction, or
stroke) in patients with acute coronary syndrome (ACS), stroke and
systemic embolism in patients with nonvalvular atrial fibrillation,
deep vein thrombosis (DVT), which may lead to pulmonary embolism
(PE) in patients who have undergone hip or knee replacement
surgery, DVT, PE, recurrent DVT and PE following initial therapy,
moderate to severe active rheumatoid arthritis in patients who have
had inadequate response or tolerance to methotrexate, acute
migraine with or without aura, chronic phase and accelerated phase
Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML)
in newly diagnosed patients or in patients resistant to or
intolerant to prior therapy that included imatinib, atrial
fibrillation (AF) in patients with a history of paroxysmal or
persistant AF or atrial flutter (AFK), who are in sinus rhythm or
will be cardioverted, asthma in patients aged 4 years and older,
airflow obstruction and reducing exacerbations in patients with
chronic obstructive pulmonary disease, erectile dysfunction (ED),
benign prostatic hyperplasia (BPH), pulmonary arterial hypertension
(PAH) (WHO Group 1) to improve exercise ability, gout flares,
Familial Mediterranean fever, antiretroviral therapy, anxiety
disorders, panic disorders, seizures, insomnia, hypertension,
cardiovascular disease, hyperlipidemia, cancer, such as primary
kidney cancer, advanced primary liver cancer, radioactive iodine
resistant advanced thyroid carcinoma, renal cell carcinoma,
imatinib-resistant gastrointestinal stromal tumor, mantle cell
lymphoma in patients who have received at least one prior therapy,
chronic lymphocytic leukemia/small lymphocytic lymphoma, chronic
lymphocytic leukemia/small lymphocytic lymphoma with 17p deletion,
Waldenstrom's macroglobulinemia, marginal zone lymphoma who require
systemic therapy and have received at least one prior
anti-CD20-based therapy, unresectable or metastatic melanoma with a
BRAF V600E or V600K mutation, allergies, transplantation,
hormone-refractory metastatic prostate cancer previously treated
with a docetaxel-containing treatment regimen, hormone-refractory
metastatic prostate cancer previously treated with a
docetaxel-containing treatment regimen, treatment of clinically
significant hypervolemic and euvolemic hyponatremia, including
patients with heart failure and Syndrome of Inappropriate
Antidiuretic Hormone (SIADH), prevention of acute and delayed
nausea and vomiting associated with initial and repeat courses of
highly emetogenic cancer chemotherapy (HEC) including high-dose
cisplatin, prevention of delayed nausea and vomiting associated
with initial and repeat courses of moderately emetogenic cancer
chemotherapy (MEC), over-active bladder with symptoms of urge
urinary incontinence, urgency, and urinary frequency, metastatic
non-small cell lung cancer (NSCLC) whose tumors have epidermal
growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R)
substitution mutations as detected by an FDA-approved test
receiving first-line, maintenance, or second or greater line
treatment after progression, locally advanced, unresectable or
metastatic pancreatic cancer, in combination with gemcitabine,
HER2-positive, metastatic breast cancer who previously received
trastuzumab and a taxane, separately or in combination in patients
who have either: received prior therapy for metastatic disease or
developed disease recurrence during or within six months of
completing adjuvant therapy, chronic, accelerated, or blast phase
Ph+ chronic myelogenous leukemia (CML) in adults with resistance or
intolerance to prior therapy, gastrointestinal stromal tumor (GIST)
after disease progression on or intolerance to imatinib mesylate,
advanced renal cell carcinoma (RCC), progressive,
well-differentiated pancreatic neuroendocrine tumors (pNET) in
patients with unresectable locally advanced or metastatic disease,
CCR5-tropic HIV-1 infection in patients 2 years of age and older
weighing at least 10 kg in combination with other antiretroviral
agents, advanced renal cell carcinoma, advanced soft tissue sarcoma
who have received prior chemotherapy, manic and mixed episodes
associated with Bipolar I, Major Depressive Disorder, irritability
associated with Autistic Disorder, Tourette's disorder, agitation
associated with schizophrenia or bipolar mania, advanced renal cell
carcinoma after failure of one prior systemic therapy, to improve
glycemic control in adults with type 2 diabetes mellitus (T2DM) who
have inadequate control with dapagliflozin or who are already
treated with dapagliflozin and saxagliptin, progressive, metastatic
medullary thyroid cancer (MTC), advanced renal cell carcinoma (RCC)
who have received prior anti-angiogenic therapy, chronic phase,
accelerated phase, or blast phase chronic myeloid leukemia (CML) or
Ph+ ALL in adults for whom no other tyrosine kinase inhibitor (TKI)
therapy is indicated, T315I-positive CML (chronic phase,
accelerated phase, or blast phase) or T315I-positive Philadelphia
chromosome in adults, positive acute lymphoblastic leukemia (Ph+
ALL), invasive aspergillosis, invasive mucormycosis, to reduce
low-density lipoprotein cholesterol (LDL-C), total cholesterol
(TC), apolipoprotein B (apo B), and non-high density lipoprotein
cholesterol (non-HDL-C) in patients with homozygous familial
hypercholesterolemia (HoFH), schizophrenia in adults, hormone
receptor (HR)-positive, human epidermal growth factor receptor 2
(HER2)-negative advanced or metastatic breast cancer in combination
with an aromatase inhibitor as initial endocrine based therapy in
postmenopausal women, or fulvestrant in women with disease
progression following endocrine therapy, Major Depressive Disorder
(MDD), suppression of motor and phonic tics in patients with
Tourette's Disorder who have failed to respond satisfactorily to
standard treatment, treatment of multiple myeloma in patients who
have received at least two prior therapies including lenalidomide
and a proteasome inhibitor and have demonstrated disease
progression on or within 60 days of completion of the last therapy,
non-small cell lung cancer (NSCLC) whose disease has not progressed
after four cycles of platinum-based first-line chemotherapy,
locally advanced or metastatic NSCLC after failure of at least one
prior chemotherapy regimen, locally advanced, unresectable or
metastatic pancreatic cancer, overactive bladder with symptoms of
urge urinary incontinence, urgency, and urinary frequency, advanced
renal cell carcinoma (RCC) after failure of treatment with
sunitinib or sorafenib, subependymal giant cell astrocytoma (SEGA)
associated with tuberous sclerosis (TS) who require therapeutic
intervention but are not candidates for curative surgical
resection, renal angiomyolipoma, tuberous sclerosis complex, in
combination with fulvestrant for the treatment of women with
hormone receptor (HR)-positive, human epidermal growth factor
receptor 2 (HER2)-negative advanced or metastatic breast cancer
with disease progression following endocrine therapy, as
monotherapy for the treatment of adult patients with HRpositive,
HER2-negative advanced or metastatic breast cancer with disease
progression following endocrine therapy and prior chemotherapy in
the metastatic setting, cystic fibrosis (CF) in patients age 2
years and older who have one mutation in the CFTR gene that is
responsive to ivacaftor based on clinical and/or in vitro assay
data, deleterious or suspected deleterious germline BRCA-mutated
advanced ovarian cancer in adult patients who have been treated
with three or more prior lines of chemotherapy, intermediate or
high-risk myelofibrosis, including primary myelofibrosis,
post-polycythemia vera myelofibrosis and post-essential
thrombocythemia myelofibrosis, polycythemia vera patients who have
had an inadequate response to or are intolerant of hydroxyurea, as
an adjunctive therapy to antidepressants for the treatment of major
depressive disorder (MDD), schizophrenia, cystic fibrosis (CF)
patients aged 12 years and older who are homozygous for the F508del
mutation or who have at least one mutation in the cystic fibrosis
transmembrane conductance regulator (CFTR) gene that is responsive
to tezacaftor/ivacaftor based on in vitro data and/or clinical
evidence, metastatic colorectal cancer (CRC) patients who have been
previously treated with fluoropyrimidine-, oxaliplatin- and
irinotecan-based chemotherapy, an antiVEGF therapy, and, if RAS
wild-type, an anti-EGFR therapy, locally advanced, unresectable or
metastatic gastrointestinal stromal tumor (GIST) patients who have
been previously treated with imatinib mesylate and sunitinib
malate, hepatocellular carcinoma (HCC) who have been previously
treated with sorafenib, use with sofosbuvir, with or without
ribavirin, for the treatment of chronic HCV genotype 1 or 3
infection, metastatic non-small cell lung cancer (NSCLC) patients
whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive
as detected by an FDA-approved test, opioid induced constipation
(OIC) in adult patients with chronic non-cancer pain, including
patients with chronic pain related to prior cancer or its treatment
who do not require frequent (e.g., weekly) opioid dosage
escalation, unresectable or metastatic melanoma with BRAF V600E
mutation as detected by an FDA-approved test, in combination with
trametinib, for the treatment of patients with unresectable or
metastatic melanoma with BRAF V600E or V600K mutations as detected
by an FDA-approved test, adjuvant treatment of patients with
melanoma with BRAF V600E or V600K mutations, as detected by an
FDA-approved test, and involvement of lymph node(s), following
complete resection, metastatic non-small cell lung cancer (NSCLC)
with BRAF V600E mutation as detected by an FDA-approved test,
locally advanced or metastatic anaplastic thyroid cancer (ATC) in
patients with BRAF V600E mutation and with no satisfactory
locoregional treatment options, and with or without ribavirin for
treatment of chronic HCV genotypes 1 or 4 infection in adults.
[0369] 125. The method of embodiment 124, wherein said CYP3A4
substrate drug is selected from the group consisting of lurasidone,
ranolazine, lumacaftor/ivacaftor, venetoclax, trabectedin,
ribociclib succinate, deflazacort, cinacalcet hydrochloride,
pimavanserin tartrate, aripiprazole lauroxil, cariprazine
hydrochloride, simeprevir sodium, everolimus, saxagliptin
hydrochloride, saxagliptin/metformin hydrochloride, ticagrelor,
vilazodone hydrochloride, apixaban, tofacitinib citrate, eletriptan
hydrobromide, nilotinib hydrochloride monohydrate, dronedarone
hydrochloride, fluticasone propionate/salmeterol xinafoate,
rivaroxaban, tadalafil, ibrutinib, cobimetinib, colchicine,
cabazitaxel, tolvaptan, fosaprepitant dimeglumine, aprepitant,
solifenacin succinate, erlotinib hydrochloride, ado-trastuzumab
ematansine, bosutinib monohydrate, sunitinib malate, fesoterodine
fumarate, maraviroc, pazopanib hydrochloride, aripiprazole,
axitinib, dapagliflozin/saxagliptin, cabozantinib S-malate,
ponatinib hydrochloride, isavuconazonium sulfate, lomitapide
mesylate, iloperidone, palbociclib, levomilnacipran hydrochloride,
pimozide, pomalidomide, abemaciclib, ivacaftor, ruxolitinib
phosphate, brexpiprazole, ivacaftor/tezacaftor, regorafenib,
daclatasvir, crizotinib, naloxegol oxalate, dabrafenib, olaparib,
and elbasvir and grazoprevir.
[0370] 126. The method of embodiment 125, wherein the CYP3A4
substrate drug is lurasidone.
[0371] 127. The method of embodiment 125, wherein the CYP3A4
substrate drug is ranolazine.
[0372] 128. The method of embodiment 125, wherein the CYP3A4
substrate drug is tadalafil.
[0373] 129. The method of any of embodiments 124-128, wherein the
patient is obese.
[0374] 130. The method of embodiment 129, wherein the patient has
at least one of the following characteristics:
[0375] i) BMI of at least about 35;
[0376] ii) % IBW of at least about 150%;
[0377] iii) waist size greater than about 42 inches;
[0378] iv) % body fat greater than about 40%;
[0379] v) total body fat greater than about 40 kg; and
[0380] vi) medically diagnosed as obese.
[0381] 131. The method of any of embodiments 124-132, wherein the
CYP3A4 substrate drug is ranolazine, and the AUC of ranolazine is
maintained at a level of no more than about a normal baseline AUC
of ranolazine to about 150% of the normal baseline AUC of
ranolazine.
[0382] 132. The method of any of embodiments 124-132, wherein the
CYP3A4 substrate drug is ranolazine, and the C.sub.max of
ranolazine is maintained at a level of no more than about a normal
baseline C.sub.max of ranolazine to about 150% of the normal
baseline C.sub.max of ranolazine.
[0383] 133. The method of any of embodiments 124-132, wherein the
CYP3A4 substrate drug is lurasidone, and the AUC of lurasidone is
maintained at a level of no more than about a normal baseline AUC
of lurasidone to about 216% of the normal baseline AUC of
lurasidone.
[0384] 134. The method of any of embodiments 124-132, wherein the
CYP3A4 substrate drug is lurasidone, and the C.sub.max of
lurasidone is maintained at a level of no more than about a normal
baseline C.sub.max of lurasidone to about 210% of the normal
baseline C.sub.max of lurasidone.
[0385] 135. The method of any of embodiments 124-132, wherein the
CYP3A4 substrate drug is tadalafil, and the AUC of tadalafil is
maintained at a level of no more than about 410% of a normal
baseline AUC of tadalafil.
[0386] 136. The method of any of embodiments 124-132, wherein the
CYP3A4 substrate drug is tadalafil, and the a C.sub.max of
tadalafil is maintained at a level of no more than about 120% of a
normal baseline C.sub.max of tadalafil.
[0387] 137. The method of any one of embodiments 134-136, wherein
the patient is a poor or intermediate CYP3A4 metabolizer.
[0388] 138. The method of any of embodiments 2, 16, 31, 45, 60, 82,
96, 111, or 125, wherein the wherein the CYP3A4 substrate drug is
erlotinib.
[0389] 139. The method of any of embodiments 2, 16, 31, 45, 60, 82,
96, 111, or 125, wherein the wherein the CYP3A4 substrate drug is
solifenacin succinate.
[0390] 140. The method of any of embodiments 2, 16, 31, 45, 60, 82,
96, 111, or 125, wherein the wherein the CYP3A4 substrate drug is
everolimus.
[0391] 141, The method of any of embodiments 2, 16, 31, 45, 60, 82,
96, 111, or 125, wherein the wherein the CYP3A4 substrate drug is
abemaciclib.
[0392] 142. The method of any of embodiments 2, 16, 31, 45, 60, 82,
96, 111, or 125, wherein the wherein the CYP3A4 substrate drug is
ivacaftor.
[0393] 143. The method of any of embodiments 2, 16, 31, 45, 60, 82,
96, 111, or 125, wherein the wherein the CYP3A4 substrate drug is
ruxolitinib phosphate.
[0394] 144. The method of any of embodiments 2, 16, 31, 45, 60, 82,
96, 111, or 125, wherein the wherein the CYP3A4 substrate drug is
brexpiprazole.
[0395] 145. The method of any of embodiments 2, 16, 31, 45, 60, 82,
96, 111, or 125, wherein the wherein the CYP3A4 substrate drug is
ivacaftor/tezacaftor.
[0396] 146. The method of any of embodiments 2, 16, 31, 45, 60, 82,
96, 111, or 125, wherein the wherein the CYP3A4 substrate drug is
regorafenib.
[0397] 147. The method of any of embodiments 2, 16, 31, 45, 60, 82,
96, 111, or 125, wherein the wherein the CYP3A4 substrate drug is
daclatasvir.
[0398] 148. The method of any of embodiments 2, 16, 31, 45, 60, 82,
96, 111, or 125, wherein the wherein the CYP3A4 substrate drug is
crizotinib.
[0399] 149. The method of any of embodiments 2, 16, 31, 45, 60, 82,
96, 111, or 125, wherein the wherein the CYP3A4 substrate drug is
naloxegol oxalate.
[0400] 150. The method of any of embodiments 2, 16, 31, 45, 60, 82,
96, 111, or 125, wherein the wherein the CYP3A4 substrate drug is
dabrafenib.
[0401] 151. The method of any of embodiments 2, 16, 31, 45, 60, 82,
96, 111, or 125, wherein the wherein the CYP3A4 substrate drug is
elbasvir and grazoprevir.
[0402] 152. The method of any of embodiments 1, 2, 6, 7, 14-16, 20,
21, 28-31, 35, 36, 43-45, 49, 50, 57-60, 64, 65, 80-82, 86, 87,
94-96, 100, 101, 108-111, 115, 116, 123-125, 129, 130, or 137-140,
wherein the CYP3A4 substrate drug is erlotinib, and the AUC of
erlotinib is maintained at a level of no more than about 164% of
the normal baseline AUC of erlotinib.
[0403] 153. The method of any of embodiments 1, 2, 6, 7, 14-16, 20,
21, 28-31, 35, 36, 43-45, 49, 50, 57-60, 64, 65, 80-82, 86, 87,
94-96, 100, 101, 108-111, 115, 116, 123-125, 129, 130, or 137-140,
wherein the CYP3A4 substrate drug is erlotinib, and the C.sub.max
of erlotinib is maintained at a level of no more than about 167% of
the normal baseline C.sub.max of erlotinib.
[0404] 154. The method of any of embodiments 1, 2, 6, 7, 14-16, 20,
21, 28-31, 35, 36, 43-45, 49, 50, 57-60, 64, 65, 80-82, 86, 87,
94-96, 100, 101, 108-111, 115, 116, 123-125, 129, 130, or 137-140,
wherein the CYP3A4 substrate drug is solifenacin succinate, and the
AUC of solifenacin succinate is maintained at a level of no more
than about 270% of the normal baseline AUC of solifenacin
succinate.
[0405] 155. The method of any of embodiments 1, 2, 6, 7, 14-16, 20,
21, 28-31, 35, 36, 43-45, 49, 50, 57-60, 64, 65, 80-82, 86, 87,
94-96, 100, 101, 108-111, 115, 116, 123-125, 129, 130, or 137-140,
wherein the CYP3A4 substrate drug is solifenacin succinate, and the
C.sub.max of solifenacin succinate is maintained at a level of no
more than about 150% of the normal baseline C.sub.max of
solifenacin succinate.
[0406] 156. The method of any of embodiments 1, 2, 6, 7, 14-16, 20,
21, 28-31, 35, 36, 43-45, 49, 50, 57-60, 64, 65, 80-82, 86, 87,
94-96, 100, 101, 108-111, 115, 116, 123-125, 129, 130, or 137-140,
wherein the CYP3A4 substrate drug is everolimus, and the AUC of
everolimus is maintained at a level of no more than about 440% of a
normal baseline AUC of everolimus.
[0407] 157. The method of any of embodiments 1, 2, 6, 7, 14-16, 20,
21, 28-31, 35, 36, 43-45, 49, 50, 57-60, 64, 65, 80-82, 86, 87,
94-96, 100, 101, 108-111, 115, 116, 123-125, 129, 130, or 137-140,
wherein the CYP3A4 substrate drug is everolimus, and the a
C.sub.max of everolimus is maintained at a level of no more than
about 200% of a normal baseline C.sub.max of everolimus.
EXAMPLES
Example 1. Pharmacokinetic Studies with Posaconazole and
Lurasidone
[0408] Inventors studied 6 obese male and female subjects (ages
18-50, BMI>35) taking Posaconazole oral tablets (300 mg qd) and
Lurasidone (20 mg qd). Body weights and BMI measurements for the 6
subjects are provided below in Table 1.
TABLE-US-00001 TABLE 1 Subject Demographics Subject # Weight (kg)
BMI (kg/m.sup.2) 101-001 111.8 45 101-002 136.8 44.4 101-005 137.7
51.2 101-007 103.7 36.8 101-008 122.3 39.8 101-010 120.0 43.9
[0409] Subjects were dosed with Lurasidone alone on Day 1, then
subsequently dosed to steady-state Posaconazole levels, with a
loading dose of 300 mg twice a day on Day 2 and 300 mg once a day
thereafter over a period of 14 days. Posaconazole administration
was then stopped and Lurasidone (20 mg qd) administered 2, 4, and 6
days after administration had ceased (studies days 17, 19, and 21
respectively). Lurasidone AUC was measured for 24 hours after each
administration. Table 2 shows subject Lurasidone AUC levels 2, 4
and 6 days after Posaconazole was stopped, Posaconazole AUC levels
2, 4, and 6 days after Posaconazole was stopped, and the ratio of
post-Posaconazole Lurasidone AUC to the baseline Lurasidone AUC
measured before Posaconazole treatment:
TABLE-US-00002 TABLE 2 Posaconazole AUC Lurasidone AUC Ratio
Subject Data Lurasidone AUC (ng * h/mL) (ng * h/mL) relative to Day
1 BMI Weight Subject Day 1 Day 17 Day 19 Day 21 Day 17 Day 19 Day
21 Day 17 Day 19 Day 21 (kg/m.sup.2) (kg) HMS001 101- 92.8 284
234.4 204.5 2886 2019 1365 3.06 2.53 2.20 45.0 111.8 001 DES005
101- 26 167.3 186 168 2512 1954 1563 6.43 7.15 6.46 51.2 137.7 005
TRB007 101- 38.3 173.8 89.5 124.7 824 542 285 4.54 2.34 3.26 36.8
103.7 007 NNJ010 101- 71 211.7 163 226 4551 3688 3081 2.98 2.30
3.18 43.9 120.0 010 KDH002 101- 110 195.5 146 186.3 1299 626 284
1.78 1.33 1.69 44.4 136.8 002 DTG008 101- 45.6 57 36.2 27.8 190 78
31 1.25 0.79 0.61 39.8 122.3 008
[0410] Table 3 compares Lurasidone AUC levels after Posaconazole
treatment to baseline Lurasidone AUC levels.
TABLE-US-00003 TABLE 3 Lurasidone Levels vs. Base Line Days After
Posaconazole Was Ceased Day 2 Day 4 Day 6 Mean 3.3x 2.7x 2.9x Min
1.3x 0.8x 0.6x Max 6.4x 7.2x 6.5x Median 3.0x 2.3x 2.7x
[0411] As shown above in Table 3, the post-Posaconazole treatment
mean AUC ratios of Lurasidone are about 3 times higher than the
baseline. This data indicates that Posaconazole accumulates in
obese subjects, and results in significantly higher Lurasidone AUC
levels compared to baseline levels measured before Posaconazole
treatment.
[0412] The AUC measurements from two patients (DTG008 and KDH002)
indicates that these patients were non-compliant with the
Posaconazole treatment regimen, and the corresponding AUC
measurements were removed from the study. The results are shown
below in Table 4.
TABLE-US-00004 TABLE 4 Lurasidone Levels vs. Base Line Days After
Posaconazole Was Ceased Excluding DTG008 & KDH002 Day 2 Day 4
Day 6 Mean 4.3x 3.6x 3.8x Min 3.0x 2.3x 2.2x Max 6.4x 7.2x 6.5x
Median 3.8x 2.4x 3.2x
[0413] These results indicate that post-Posaconazole treatment mean
AUC ratio values for Lurasidone are in the range of from
3.6-4.3.times. for 2-6 days after ceasing Posaconazole
treatment.
[0414] In conclusion, the results from the clinical trials reported
in Example 1 indicate that the Posaconazole accumulates in the body
of obese patients after treatment has stopped, and patients should
delay a first dose of Lurasidone or reduce the first dose of
Lurasidone to achieve safe blood plasma levels of Lurasidone.
Example 2. Sustained Impairment of Lurasidone Clearance after
Discontinuation of Posaconazole. Impact of Obesity, and
Implications for Patient Safety
[0415] The following studies were reported by Greenblatt et al., J.
Clin. Psychopharmacol., 2018; 38(4):289-295 (doi:
10.1097/JCP.0000000000000892), which is herein incorporated by
reference in its entirety for all purposes.
[0416] The antipsychotic agent lurasidone is metabolized by
Cytochrome P450-3A (CYP3A) enzymes. Coadministration with strong
CYP3A inhibitors (such as ketoconazole, posaconazole, and
ritonavir) is contraindicated due to the risk of sedation and
movement disorders from high levels of lurasidone. This study
evaluated the time-course of recovery from the posaconazole drug
interaction, and the effect of obesity on the recovery process.
[0417] With posaconazole coadministration, lurasidone area under
the concentration curve (AUC) increased by an arithmetic mean
factor of 6.2 in normals, and by 4.9 in obese subjects.
Post-treatment washout of posaconazole was slow in normals (mean
half-life 31 hours), and further prolonged in obese subjects (53
hours). Recovery of lurasidone AUC toward baseline was
correspondingly slow, and was incomplete. AUC remained
significantly elevated above baseline both in normals (factor of
2.1) and obese subjects (factor of 3.4) even at 2 weeks after
stopping posaconazole.
[0418] Product labeling does not address the necessary delay after
discontinuation of a strong CYP3A inhibitor before lurasidone can
be safely administered. It is recommended that normal-weight and
obese patients be required to limit the dosage of lurasidone, or
undergo a washout period after discontinuation of posaconazole, as
set forth in the present disclosure.
[0419] Methods. Study Site and Institutional Review Board. The
study was conducted at Avail Clinical Research, located in DeLand,
Fla. The study protocol and consent document were reviewed and
approved by IntegReview, Austin, Tex. All study participants
provided written informed consent prior to initiation of any study
procedures. In addition, this study was performed in accordance
with the Declaration of Helsinki, International Conference on
Harmonization Good Clinical Practice guidelines, and applicable
regulatory requirements.
[0420] Subjects. The study participants consisted of two cohorts,
with a total of 34 subjects receiving at least one dose of study
drug, and a total of 24 subjects completing the entire study with
evaluable pharmacokinetic data. In the first cohort were those of
normal body habitus (n=11 completed; BMI 18.5-24.9 kg/m.sup.2,
inclusive); the second group consisted of subjects of obese body
habitus (n=13 completed; BMI.gtoreq.35 kg/m.sup.2). Subjects were
previously known to the research center, or were recruited through
notices in the public media. Subjects were matched by gender and
age when possible. Sample sizes were based on power
calculations.
[0421] Potential participants underwent screening and evaluation
within 30 days of study initiation. Procedures included medical and
psychiatric history, physical examination, electrocardiogram if
indicated, hematologic and biochemical screening (including liver
function tests such as alanine transaminase, asparagine
transaminase, and bilirubin), and urine testing for drugs of abuse.
All study participants were healthy, active, non-smoking adults
with no history of significant medical or psychiatric disease and
taking no prescription medications. Obese subjects were free of
metabolic or other complications of obesity. Potentially
child-bearing women in both groups had negative pregnancy tests and
agreed to avoid the risk of pregnancy during the course of the
study. Subjects were instructed to avoid alcohol use throughout the
course of the study and underwent a breath alcohol analysis prior
to initiation of the study protocol.
[0422] Subjects' waist circumference was measured manually. Percent
android fat for all subjects was determined by dual energy X-ray
absorptiometry (DXA). For three subjects whose weight exceeded the
limits of the DXA instrumentation, percent android fat was imputed
using population data available from the National Health and
Nutrition Evaluation Survey (NHANES). Total android fat (termed
total body fat) was calculated as the product of body weight and
percent android fat. Ideal body weight (IBW) was determined from
actuarial data based on height and gender, and percent ideal body
weight calculated as the ratio of actualweight divided by IBW.
[0423] Procedures. Subjects received lurasidone (20 mg tablet) on
the mornings of study Days 1, 14, 20, 23, 26, and 30. Lurasidone
doses were given immediately prior to a continental breakfast
provided in the clinical research unit. Venous blood samples were
drawn into ethylenediaminetetraacetic acid (EDTA)-containing tubes
from an indwelling catheter, or by separate venipuncture, prior to
the lurasidone dose and at 1, 2, 3, 4, 8, 12, 18, 24, 48, and 72
hours post-dose. Samples were centrifuged and the plasma was
separated and frozen at -70.degree. C. until the time of assay.
[0424] On study Day 4, subjects received two doses of posaconazole
(300 mg BID). On the mornings of Days 5-17, they received
posaconazole 300 mg once daily. As posaconazole is to be taken with
food, subjects were fed a continental breakfast in the clinical
research unit after receiving posaconazole and prior to discharge
from the unit. Venous blood samples were drawn into EDTA containing
tubes prior to the posaconazole dose on Days 4, 7, 11, and prior to
the lurasidone dose on Days 14, 20, 23, 26 and 30. An additional
blood sample was taken 5 hours after posaconazole dosage on Day 17,
for approximate determination of maximum posaconazole plasma
concentrations, and on Day 33. Samples were centrifuged and the
plasma was separated and frozen at -70.degree. C. until the time of
assay.
[0425] Analytic Methods. All bioassay analyses were performed by
Keystone Bioanalytical, North Wales, Pa. For analysis of
posaconazole, the internal standard (posaconazole-D4) was added to
the biological samples. Plasma samples were precipitated using
formic acid in acetonitrile and isolated using a Phree phospholipid
removal tube. An aliquot of the sample was injected onto a
high-pressure liquid chromatograph with tandem mass spectrometry
triple quadrupole mass spectrometer (SCIEX API-5500). The
analytical column was a Unison CK-218, 3 .mu.m particle size HPLC
column (50.times.2 mm) from Imtakt USA (Portland, Oreg.). The
mobile phase consisted of an aqueous component (0.25% formic acid
and 10 mM ammonium formate in water) and an organic component (0.1%
formic acid in acetonitrile) and was delivered by gradient, with
the organic component going from 35% to 100%. The m/z transitions
monitored were 701.6>614.4 for posaconazole and 705.6>618.4
for the internal standard. The calibration curve ranged from 1-1000
ng/mL (8 concentrations in duplicate).
[0426] For analysis of lurasidone, the internal standard
(lurasidone-D8) was added to the biological samples. Plasma samples
were isolated using a Phree phospholipid removal tube. An aliquot
of the sample was injected onto a high-pressure liquid
chromatograph with tandem mass spectrometry triple quadrupole mass
spectrometer (SCIEX API-5500). The analytical column was a Unison
UK-C18, 3 .mu.m particle size HPLC column (50.times.2 mm) from
Imtakt USA (Portland, Oreg.). The mobile phase consisted of an
aqueous component (0.025% formic acid and 10 mM ammonium formate in
water) and an organic component (0.1% formic acid in acetonitrile)
and was delivered by gradient, with the organic component going
from 35% to 100%. The m/z transitions monitored were 493.4>166.1
for lurasidone and 501.4>166.1 for the internal standard. The
calibration curve ranged from 0.25-200 ng/mL (8 concentrations in
duplicate).
[0427] Pharmacokinetic and Statistical Methods. For each subject,
pre-dose plasma posaconazole concentrations on study Days 14 and 17
were averaged, and used as a steady-state concentration (C.sub.ss)
to calculate apparent steady-state clearance of posaconazole
according to the relation: Clearance=(dosing rate)/C.sub.ss. The
apparent washout half-life of posaconazole was calculated by
log-linear regression analysis starting with the plasma
concentration on Day 20 and ending with the last non-zero value.
Differences between normal-weight and obese cohorts were evaluated
by Student's t-test for independent groups. The relation between
measures of body habitus and posaconazole washout half-life for
individual subjects was evaluated by linear regression
analysis.
[0428] For each lurasidone trial for each subject, the terminal
log-linear phase of the plasma concentration curve was identified
visually, and the terminal rate constant (beta) was determined by
log-linear regression analysis. This was used to calculate the
elimination half-life. Area under the plasma concentration curve
from time zero until the last non-zero point was determined by the
linear trapezoidal method. To this was added the residual area,
calculated as the final non-zero concentration divided by beta,
yielding the total area under the plasma concentration curve
extrapolated to infinity (AUC). Also tabulated was the observed
maximum plasma concentration (C.sub.max). AUC and C.sub.max both
were adjusted, where necessary, for non-zero baseline (pre-dose)
concentrations measured in some subjects on the Day 20, 23, 26, and
30 trials.
[0429] Variables were aggregated as arithmetic mean and SD or SE.
Lurasidone C.sub.max and AUC were also aggregated as geometric mean
and 90% confidence interval (90% CI). Differences in kinetic
variables between study Day 1 and Days 14, 20, 23, 26, and 30
(control vs after posaconazole administration) were evaluated
either from the untransformed data using Dunnett's t-test, or by
comparison of geometric means and the 90% CI of the difference.
[0430] The relation between lurasidone AUC and plasma posaconazole
concentration for individual subjects across the 5 DDI trials (Days
14, 20, 23, 26, and 30) was analyzed by nonlinear regression (SAS
PROC NLIN). The following function was fitted to data points:
Y=Y.sub.0+BX.sup.A
where Y is the lurasidone AUC value corresponding to X, the plasma
posaconazole concentration at the start of relevant AUC measurement
period. Iterated variables were: Y.sub.0, A, and B.
[0431] Results
[0432] Subject Characteristics. Screening procedures yielded 34
subjects who were potential study participants. Of these, 8
initiated participation but did not complete the study for personal
or administrative reasons not related to the study or study
medications. Data from 2 other subjects could not be analyzed due
to apparent protocol deviations. A total of 24 subjects (11
normal-weight and 13 obese) completed the study and were included
in the pharmacokinetic analysis (Table 5). The groups were
comparable in age, gender composition, height, and IBW. The obese
group had significantly higher values of weight, percent IBW, BMI,
waist circumference, percent android fat, and total body (android)
fat (Table 5). The mean weight in the obese group s 140 kg (309
pounds), and the mean BMI was 49.3 kg.
TABLE-US-00005 TABLE 5 DEMOGRAPHIC CHARACTERISTICS OF STUDY
PARTICIPANTS Independent Normal- t-test: weight* Obese* Normal vs
obese Number 11 13 Age (years) 34 .+-. 8 33 .+-. 7 N.S. Male/female
6/5 6/7 Weight (Kg) 67.9 .+-. 9.1 140.4 .+-. 32.sup. P < 0.001
(Pounds) 149 .+-. 29 309 .+-. 70 P < 0.001 Height (Cm) 171 .+-.
10 168 .+-. 11 N.S. (Inches) 67.3 .+-. 4.0 66.3 .+-. 4.3 N.S. BMI
(kg/m.sup.2) 23.1 .+-. 1.8 49.3 .+-. 9.6 P < 0.001 Waist
circumference (Cm) 80.4 .+-. 6.8 129.3 .+-. 22.4 P < 0.001
(Inches) 31.7 .+-. 2.7 50.9 .+-. 8.8 P < 0.001 Ideal body weight
(kg) 64.5 .+-. 12.3 61.9 .+-. 11.4 N.S. Percent ideal body 106 .+-.
11 230 .+-. 46 P < 0.001 weight Percent android fat 33 .+-. 12
66 .+-. 4 P < 0.001 Total body fat (kg) 22.5 .+-. 8.0 81.3 .+-.
25.8 P < 0.001 *Mean .+-. SD
[0433] Adverse Events. Five subjects experienced adverse events
considered possibly or probably related to one or both study
medications. These were gastrointestinal disturbances in two cases,
and one each of dry mouth, somnolence, and headache. All resolved
without specific treatment.
[0434] Posaconazole Pharmacokinetics. Plasma posaconazole
concentrations had reached steady-state by study Day 14 (FIG. 1).
Mean C.sub.ss was significantly lower, and posaconazole clearance
was significantly higher, in the obese cohort compared to controls
(Table 6). However, weight-normalized posaconazole clearance was
not significantly different between the groups.
[0435] Washout of posaconazole after discontinuation of treatment
was significantly slower in the obese group compared to controls
(P<0.005) (FIG. 1). Mean washout half-life values in the two
groups were 2.19 days (52.5 hours) and 1.28 days (31 hours),
respectively (Table 6). Among all subjects, the correlation between
posaconazole washout half-life and each of the measures of body
habitus was statistically significant, but the degree of obesity
explained only a small fraction of variance in washout
half-life(r2<0.32). The attenuated associations were in part
attributable to two obese subjects with very long half-life values
(121 hours).
TABLE-US-00006 TABLE 6 POSACONAZOLE PHARMACOKINETICS Mean .+-. SD
value for Group: Value of Student's t: Normal Obese Normal vs Obese
Steady-state 2377 .+-. 1188 1462 .+-. 649 3.33 (P < 0.005)
concentration (ng/mL) Steady-state clearance mL/min 101 .+-. 71 175
.+-. 91 2.19 (P < 0.04) mL/min/kg 1.48 .+-. 1.02 1.25 .+-. 0.61
N.S. Washout 31 .+-. 6.7 52.5 .+-. 31.1 2.25 (P < 0.04)
half-life (hours)
[0436] Lurasidone Pharmacokinetics. Coadministration of lurasidone
with posaconazole resulted in a highly significant increase in
lurasidone C.sub.max and AUC (FIG. 2, Table 7). Comparing Day 14
values to the Day 1 pre-posaconazole values based on ratio of
geometric means, C.sub.max increased by a factor of 4.0 in
normal-weight subjects and by 2.9 in the obese subjects.
Corresponding increases in AUC were greater than increases in
C.sub.max. Geometric mean AUC increased by a factor of 5.75 in the
normal-weight cohort, and by 4.34 in the obese cohort (Table 7).
When calculated as arithmetic mean ratios, values were 6.2 in
controls and 4.9 in obese subjects.
TABLE-US-00007 TABLE 7 SUMMARY OF LURASIDONE PHARMACOKINETICS Ratio
of geometric Arithmetic mean .+-. standard error Geometric mean
(90% CI) means (RGM) vs Day 1 (90% CI) Corrected Cmax (ng/mL)
Corrected Cmax (ng/mL) Corrected Cmax Normal Obese Normal Obese
Normal Obese Day 1 17.1 .+-. 1.6 19.8 .+-. 4 16.3 (13.5-19.6) 15.1
(10.2-22.6) Day 14 69.4 .+-. 8.3* 47.0 .+-. 5* 65.2 (53.5-79.5)
44.1 (35.9-54.2) Day 14 4.00 (3.09-5.19) 2.91 (1.89-4.47) Day 20
55.9 .+-. 7.8* 40.0 .+-. 5* 48.6 (34.6-68.4) 36.6 (29-46.3) Day 20
2.98 (2.06-4.33) 2.42 (1.55-3.76) Day 23 42.5 .+-. 6.3* 30.0 .+-. 3
37.8 (28.5-50.2) 28.0 (22.7-34.6) Day 23 2.32 (1.68-3.21) 1.85
(1.2-2.84) Day 26 32.2 .+-. 6.6 30.0 .+-. 4 26.5 (18.3-30.9) 26.9
(21-34.5) Day 26 1.63 (1.1-2.4) 1.78 (1.13-2.79) Day 30 26.2 .+-.
3.2 25.0 .+-. 4.4 24.0 (18.6-30.9) 21.6 (16.4-28.4) Day 30 1.47
(1.09-1.99) 1.42 (0.89-2.26) Total AUC (ng/mL .times. hr) Total AUC
(ng/mL .times. hr) Total AUC Normal Obese Normal Obese Normal Obese
Day 1 57.9 .+-. 5.8 50.8 .+-. 9 54.5 (43.3-68.6) 42.0 (30.4-57.9)
Day 14 333 .+-. 24* 205 .+-. 19* 324 (282-372) 195 (166-230) Day 14
5.94 (4.64-7.46) 4.66 (3.28-6.59) Day 20 265 .+-. 34* 217 .+-. 20*
237 (175-321) 205 (173-244) Day 20 4.34 (3-6.28) 4.90 (3.45-6.96)
Day 23 204 .+-. 27* 170 .+-. 17* 184 (139-242) 160 (133-193) Day 23
3.38 (2.39-4.78) 3.82 (2.68-5.47) Day 26 148 .+-. 27* 152 .+-. 19*
122 (83-179) 140 (113-173) Day 26 2.24 (1.45-3.46) 3.33 (2.3-4.83)
Day 30 129 .+-. 20* 150 .+-. 17* 114 (85-154) 140 (116-170) Day 30
2.10 (1.46-3.01) 3.34 (2.33-4.78) *P < 0.05 compared to Day 1
value, Dunnett's t test
[0437] Kinetic variables for lurasidone recovered toward the
pre-posaconazole baseline values during the posaconazole washout
period. Based on ratios of geometric mean values versus the Day 1
baseline, C.sub.max remained elevated above Day 1 even on Day 30
(ratio=1.47, 90% CI=1.09-1.99) in the normal-weight control
subjects. In the obese cohort, C.sub.max remained above baseline up
to Day 26. Recovery of AUC in both groups was even less complete,
with Day 30 ratios of 1.9 in the normal-weight group and 2.8 in the
obese subjects (arithmetic mean ratios: 2.1 and 3.4, respectively).
Consistent with the slower washout of posaconazole in the obese
group, the rate of recovery of lurasidone AUC toward baseline
values was correspondingly slower in the obese cohort compared to
controls (FIG. 3).
[0438] Baseline values of lurasidone elimination half-life averaged
9.4 hours in normal-weight subjects and 10.9 hours in the obese
group. These values are in the range of what has been reported
previously. The half-life values were significantly prolonged
during and after administration of posaconazole, and were still
substantially longer than baseline values even on the Day 30 trial
(FIG. 2, Table 8). Mean half-life values were longer in obese
subjects compared to controls. However, half-life determinations
were complicated by estimates that exceeded the sampling duration
in some subjects.
TABLE-US-00008 TABLE 8 LURASIDONE ELIMINATION HALF-LIFE (HOURS)
Arithmetic mean .+-. S.E. Normal Obese Day 1 9.4 .+-. 1.5 10.9 .+-.
4 Day 14 37 .+-. 4* 38 .+-. 2* Day 20 39 .+-. 3* 48 .+-. 4* Day 23
48 .+-. 5* 52 .+-. 3* Day 26 50 .+-. 7* 61 .+-. 4* Day 30 45 .+-.
9* 71 .+-. 5* *P < 0.05 compared to Day 1 based on Dunnett's t
test
[0439] Relation of Plasma Posaconazole to Lurasidone AUC. Based on
analysis of data from all subjects, individual variations in plasma
posaconazole concentrations accounted for 66% of the variance in
lurasidone AUC at the corresponding times (r.sup.2=0.66),
indicating that posaconazole exposure is a principal determinant of
the magnitude of the posaconazole-lurasidone DDI (FIG. 4).
[0440] Discussion. The present study evaluated the pharmacokinetic
DDI between lurasidone as victim (substrate) and the strong CYP3A
inhibitor posaconazole as perpetrator (precipitant), both in
volunteers of normal body weight and in an otherwise healthy group
of subjects with BMI.gtoreq.35 kg/m2. A particular focus of the
study was the time-course of recovery from the DDI during the two
weeks after discontinuation of posaconazole.
[0441] Coadministration of lurasidone with typical doses of
posaconazole resulted in increased lurasidone exposure (total AUC)
by a factor averaging in the range of 4 to 6 in both groups of
subjects. After posaconazole was discontinued, the effect on
lurasidone exposure did not return quickly to baseline. Rather, the
DDI persisted for at least 2 weeks after the last dose of
posaconazole, and probably well beyond the study duration. The slow
recovery from the DDI was consistent with the long elimination
half-life of posaconazole. With all data aggregated, plasma
posaconazole concentration accounted for 66% of the variability in
lurasidone AUC associated with the DDI.
[0442] The pharmacokinetic properties of posaconazole were
significantly modified in the cohort of obese subjects compared to
those of normal body size. The clearance of posaconazole--not
corrected for body weight--was higher in obese subjects compared to
controls, resulting in lower values of C.sub.ss when the same daily
dosage was administered to both groups. Despite the higher
clearance, the washout half-life was significantly prolonged in the
obese subjects compared to controls. This is likely explained by
the disproportionate distribution of the lipophilic drug
posaconazole into excess adipose tissue, thereby causing a
prolongation of elimination half-life. As a result of the longer
half-life and persistence of posaconazole in blood, the duration of
the lurasidone DDI was correspondingly longer. At two weeks after
the last dose of posaconazole, lurasidone AUC was still elevated
above baseline by a mean factor of 3.3 in the obese subject
group.
[0443] This study involved a relatively small number of subjects,
but the findings were statistically robust. Although lurasidone was
administered as single test doses, the kinetics of lurasidone are
linear, and single-dose kinetic properties will be predictive of
behavior during multiple dosing as is customary in the treatment of
schizophrenia.
[0444] Conclusions. The posaconazole-lurasidone DDI persists long
after posaconazole is discontinued, resulting in a sustained risk
of a potentially hazardous DDI. The duration of persistent risk is
further prolonged in obese individuals due to the effect of obesity
on the elimination kinetics of posaconazole. Revision of product
labeling is needed to assure patient safety. Based on the findings
of this study, it is recommended to require normal-weight and obese
patients to limit the dosage of lurasidone, or undergo a washout
period, as set forth in the present disclosure.
Example 3. Persistence of a Posaconazole-Mediated Drug-Drug
Interaction with Ranolazine after Cessation of Posaconazole
Administration: Impact of Obesity and Implications for Patient
Safety
[0445] The following studies were reported by Chow et al., J. Clin.
Pharmacology. 2018; 0(0):1-7 (doi: 10.1002/jcph.1257), which is
herein incorporated by reference in its entirety for all
purposes.
[0446] The antianginal agent ranolazine is metabolized primarily by
cytochrome P450-3A (CYP3A) enzymes. Coadministration with strong
CYP3Ainhibitors, such as ketoconazole and posaconazole, is
contraindicated due to risk of QT prolongation from high levels of
ranolazine. This study evaluated the time course of recovery from
the posaconazole drug interaction in normal-weight and otherwise
healthy obese subjects. Subjects received single doses of
ranolazine in the baseline control condition, again during
coadministration of posaconazole, and at 4 additional time points
during the 2 weeks after posaconazole discontinuation. With
posaconazole coadministration, the geometric mean ratio of
ranolazine area under the concentration curve (AUC) increased by a
factor of 3.9 in normals and by 2.8 in obese subjects.
Posttreatment washout of posaconazole was slow in normals (mean
half-life 36 hours) and further prolonged in obese subjects (64
hours). Recovery of ranolazine AUC toward baseline was delayed. AUC
remained significantly elevated above baseline in normal-weight and
obese subjects for 7-14 days after stopping posaconazole. Current
product labeling does not address the need for delay or a reduced
dose of ranolazine after discontinuation of a strong CYP3A
inhibitor before ranolazine can be safely administered. It is
recommended that administration of ranolazine should be limited,
for example to 500 mg twice daily for 7 days after posaconazole
discontinuation in patients with body mass index 18.5-24.9 kg/m2
and for 12 days in patients with body mass index .gtoreq.35
kg/m.sup.2 after ranolazine is resumed.
[0447] Methods. Study Site and Institutional Review Board. The
study was conducted at Avail Clinical Research, located in DeLand,
Fla. The study protocol and consent document were reviewed and
approved by IntegReview, Austin, Tex. All study participants
provided written informed consent prior to initiation of any study
procedures. In addition, this study was performed in accordance
with the Declaration of Helsinki, International Conference on
Harmonisation Good Clinical Practice guidelines, and applicable
regulatory requirements.
[0448] Subjects. A total of 30 subjects, aged 19 to 50, were
enrolled in the study (Table 9). All were healthy adults without
evidence of active medical disease, with the exception of obesity,
and taking no prescription medications; 43% of the study subjects
were male.
[0449] The study included 2 cohorts of volunteers. The first
consisted of subjects of normal body habitus (BMI 18.5-24.9
kg/m.sup.2, inclusive, n 15); the second consisted of subjects of
obese body habitus (BMI 2:35 kg/m.sup.2, n 15). Subjects were
matched by sex and age when possible. Sample sizes were based on
power calculations.
[0450] Potential study participants underwent screening and
evaluation within 30 days of study initiation. Procedures included
medical and psychiatric history, physical examination,
electrocardiogram (ECG), hematologic and biochemical screening, and
urine testing for drugs of abuse. All study participants were
healthy active nonsmoking adults with no history of significant
medical or psychiatric disease and taking no prescription
medications. Obese subjects were free of metabolic or other
complications of obesity. Potentially child-bearing women in both
groups had a negative pregnancy test and agreed to avoid the risk
of pregnancy during the course of the study. Subjects were also
administered 12-lead ECGs in triplicate on study days 1 and 15
before and 4 hours after the ranolazine dose as well as before
discharge on day 30.
[0451] Subjects' waist circumference was measured manually.
Percentage android fat for all subjects was determined by
dual-energy x-ray absorptiometry. Total android fat (total body
fat) was calculated as the product of body weight and percentage
android fat.
[0452] Procedures. Subjects received ranolazine (500 mg
extended-release tablet) on the mornings of study days 1, 15, 18,
22, 25, and 29. Venous blood samples were drawn into
ethylenediaminetetraacetic acid (EDTA)-containing tubes from an
indwelling catheter or by separate venipuncture prior to the
ranolazine dose and at 1, 2, 4, 6, 8, 12, 18, 24, and 32 hours
postdose. Samples were centrifuged, and the plasma was separated
and frozen at -70.degree. C. until the time of assay of plasma
ranolazine concentrations.
[0453] On study day 2, subjects received posaconazole (300 mg
delayed-release tablet twice a day), and on the mornings of days
3-15, subjects received posaconazole (300 mg delayed-release tablet
daily). Because posaconazole is to be taken with food,.sup.6
subjects were fed a continental breakfast in the clinical research
unit after receiving posaconazole and before discharge from the
unit. Venous blood samples were drawn into EDTA-containing tubes
before the posaconazole dose on days 2, 5, 8, 12, and 15, and
before the ranolazine dose on days 18, 22, 25, and 29. One
additional blood sample was taken 5 hours after the posaconazole
dose on day 15 for approximate determination of maximum plasma
posaconazole concentrations. Samples were centrifuged, and the
plasma was separated and frozen at -70.degree. C. until the time of
assay of plasma posaconazole concentrations.
[0454] Analytic Methods. All bioassay analysis was performed by
Keystone Bioanalytical (North Wales, Pa.). For analysis of
posaconazole, the internal standard (posaconazole-d.sub.4) was
added to the biological samples. Plasma samples were precipitated
using formic acid in acetonitrile and isolated using a Phree
phospholipid removal tube, and then an aliquot of the sample was
injected onto a high-pressure liquid chromatography with tandem
mass spectrometry triple quadrupole mass spectrometer (Sciex
API-5500). The analytical column was a Unison CK-218, 3 .mu.m
particle size HPLC column (50.times.2 mm) from Imtakt USA
(Portland, Oreg.). The mobile phase consisted of an aqueous
component (0.25% formic acid and 10 mmol/L ammonium formate in
water) and an organic component (0.1% formic acid in acetonitrile)
and was delivered by gradient, with the organic component going
from 35% to 100%. The m/z transitions monitored were
701.6.fwdarw.614.4 for posaconazole and 705.6.fwdarw.618.4 for the
internal standard. The calibration curve ranged from 1 to 1000
ng/mL (8 concentrations in duplicate). The interassay precision of
this method (as percentage coefficient of variance) was 4.28% to
7.14%, and the interassay accuracy (as percentage relative error)
was 7.02% to 3.12%.
[0455] For analysis of ranolazine in plasma samples, the internal
standard (ranolazine-d3) was added to the biological samples.
Plasma samples were extracted by methyl tertiary butyl ether,
centrifuged, and the upper layer was transferred to plastic
injection vials with MeOH/water (50:50). An aliquot of the sample
was then injected onto a high-pressure liquid chromatography with
tandem mass spectrometry triple quadrupole mass spectrometer (Sciex
API-5500). The analytical column was a Unison CK-218, 3 .mu.m
particle size HPLC column (50.times.2 mm) from Imtakt USA
(Portland, Oreg.). The mobile phase consisted of an aqueous
component (0.025% formic acid and 10 mmol/L ammonium formate in
water) and organic component (0.1% formic acid in acetonitrile) and
was delivered by gradient, with the organic component going from
15% to 45%. The m/z transitions monitored were 428.3.fwdarw.279.2
for ranolazine and 431.3.fwdarw.282.2 for the internal standard.
The calibration curve ranged from 5 to 2500 ng/mL (8 concentrations
in duplicate). The interassay precision of this method (as
percentage coefficient of variance) was 1.49% to 4.88%, and the
intra-assay accuracy (as percentage relative error) was -3.07% to
1.83%.
[0456] Pharmacokinetic and Statistical Methods. For each ranolazine
trial in each subject, the terminal log-linear phase of the plasma
concentration curve was identified visually, and the terminal rate
constant (.beta.) was determined by log-linear regression analysis.
This was used to calculate the half-life (t.sub.1/2). The area
under the plasma concentration curve from time 0 until the last
nonzero point was determined by the linear trapezoidal method. To
this was added the residual area, calculated as the final nonzero
concentration divided by .beta., yielding the total area under the
plasma concentration curve extrapolated to infinity (AUC). Also
tabulated was the observed maximum plasma concentration
(C.sub.max). Variables were aggregated as arithmetic mean and SD.
Ranolazine C.sub.max and AUC were also aggregated as geometric mean
and 90% CI.
[0457] For each subject, the predose plasma posaconazole
concentration on study day 15 was used as a steady-state
concentration. The apparent washout half-life of posaconazole was
calculated by log-linear regression analysis starting with the
plasma concentration on day 15 and ending with the last nonzero
value. Differences between normal-weight and obese cohorts were
evaluated by Student t-test for independent groups.
[0458] Differences in kinetic variables between study days 1 and
15, 18, 22, 25, and 29 (control versus after posaconazole
administration) were evaluated either from the untransformed data
using Dunnett's t-test or by comparison of geometric means and the
90% CI of the difference.
[0459] QTcF values were determined electronically from 12-lead ECG
readings taken for safety purposes. This protocol did not involve a
thorough QT study; however, safety data were recorded, and the
mean, standard deviation, and standard error of QT and QTcF values
were tabulated. Differences between baseline and study days 1, 15,
and 30 were evaluated by Student's t-test for independent
groups.
[0460] Results. All 30 subjects completed day 1 of the study, and
27 completed the full study protocol. (One subject was
inadvertently given an incorrect dosage of study drug on day 1;
this subject was allowed to re-enroll with a new subject number
after an appropriate washout period.) Two obese subjects and 1
normal-weight subject withdrew from the study before completion of
all study procedures. In the normal-weight group, 1 subject
discontinued due to abdominal pain that was possibly related to
ranolazine treatment. In the obese group, 1 subject withdrew
consent for personal reasons, and 1 subject discontinued due to an
adverse event (paresthesia) that was unrelated to the study
drug.
[0461] Obese subjects were similar in height to normal-weight
subjects but were significantly higher in age, weight, BMI, and
percentage of total body fat (Table 9).
TABLE-US-00009 TABLE 9 Demographic characteristics of study
participants (mean .+-. SD) Normal-weight Obese Number 14 13 Age
(years) 27.7 .+-. 10.6 33.9 .+-. 7.7 Male/female 7/7 4/9 Weight
(Kg) 71.2 .+-. 8.2 116.8 .+-. 19.6 (Pounds) .sup. 157 .+-. 18.1
257.5 .+-. 43.2 Height (Cm) 174.0 .+-. 8.6 169.0 .+-. 11.8 (Inches)
68.5 .+-. 3.4 66.5 .+-. 4.6 BMI (kg/m.sup.2) 23.5 .+-. 1.6 40.9
.+-. 5.7
[0462] Posaconazole plasma concentrations were lower in obese
subjects than in normal-weight subjects (FIG. 5); however, this
difference did not reach significance. This is consistent with
previous observations of altered posaconazole pharmacokinetics in
obese subjects compared to normal-weight subjects, where
posaconazole plasma concentrations were observed to be lower in
obese patients. Trough (predose) steady-state posaconazole
concentrations on day 15 were 3071.+-.1422 ng/mL in normal-weight
subjects and 2258.+-.952 ng/mL in obese subjects. Surprisingly,
however, it was also observed that the postdosage washout half-life
of posaconazole in obese subjects was significantly increased
relative to that in normal-weight subjects (64.3 hours and 35.8
hours, respectively). Posaconazole plasma concentrations persisted
for at least 2 weeks after stopping treatment in most subjects
(FIG. 5).
[0463] The geometric mean AUC for ranolazine on day 1 was similar
in normal-weight and obese subjects (6454 ng h/mL and 6955 ng h/mL,
respectively). Similarly, the geometric mean C.sub.max on day 1 did
not differ significantly between groups (664.7.+-.318.2 ng/mL and
559.1.+-.270.7 ng/mL in normal-weight and obese subjects,
respectively). The geometric mean AUC and Cmax for ranolazine in
both normal-weight and obese subjects on days 15, 18, and 22
increased significantly compared to day 1 (FIG. 6, Table 10). AUC
and Cmax did not differ significantly between groups. t1/2 on day 1
was slightly prolonged in obese subjects (4.99.+-.1.50 hours and
6.02.+-.1.75 hours in normal-weight and obese subjects,
respectively), but this difference did not reach significance
(P=0.126, Table 10).
TABLE-US-00010 TABLE 10 Pharmacokinetic parameters of ranolazine
(mean .+-. SD) Normal-weight Obese Day 1 C.sub.max (ng/mL) 665 .+-.
318 559 .+-. 271 AUC.sub.0-inf (ng/mL .times. h) 7085 .+-. 3603
8126 .+-. 4840 T.sub.1/2 (h) 4.98 .+-. 1.50.sup.a 6.02 .+-.
1.75.sup.a Day 15 C.sub.max (ng/mL) 1429 .+-. 666* 1177 .+-. 512*
AUC.sub.0-inf (ng/mL .times. h) 27477 .+-. 14895* 25842 .+-. 21638*
T.sub.1/2 (h) 9.54 .+-. 4.3 8.78 .+-. 5.58 Day 18 C.sub.max (ng/mL)
1188 .+-. 469* 1096 .+-. 502* AUC.sub.0-inf (ng/mL .times. h) 17310
.+-. 10263* 19294 .+-. 14150* T.sub.1/2 (h) 5.73 .+-. 1.53 7.93
.+-. 2.98 Day 22 C.sub.max (ng/mL) 974 .+-. 400* 1063 .+-. 508*
AUC.sub.0-inf (ng/mL .times. h) 13414 .+-. 6252* 15920 .+-. 11832*
T.sub.1/2 (h) 6.47 .+-. 3.14 6.09 .+-. 2.10 Day 25 C.sub.max
(ng/mL) 928 .+-. 482* 976 .+-. 487* AUC.sub.0-inf (ng/mL .times. h)
9385 .+-. 4591 13846 .+-. 10600 T.sub.1/2 (h) 5.05 .+-. 1.82 6.07
.+-. 2.10 Day 29 C.sub.max (ng/mL) 751 .+-. 276 719 .+-. 333
AUC.sub.0-inf (ng/mL .times. h) 8568 .+-. 3802 10171 .+-. 7942
T.sub.1/2 (h) 4.45 .+-. 1.38 6.38 .+-. 3.05 *Significance vs Day 1
determined by Dunnett's t-test .sup.aNot significant between
normal-weight and obese groups (p = 0.126) by Student's t-test
[0464] Within each cohort, the interaction between posaconazole and
ranolazine was greatest on day 15 relative to day 1 as determined
by the AUC geometric mean ratio (GMR) and 90% CI. The magnitude of
the interaction decreased from days 18 to 29; however, plasma
ranolazine concentrations on day 29 were still increased relative
to day 1 (FIG. 7, Table 11). The lower bound of the AUC GMR 90% CI
also remained above 1.0 for 7 days in both normal-weight and obese
subjects. Cmax GMRs and 90% CIs followed a similar trend and can be
found in Table 11.
TABLE-US-00011 TABLE 3 Geometric mean ratios (90% CI) of plasma
ranolazine Normal-weight Obese Day 15/Day 1 AUC.sub.0-inf 3.88
(2.94-5.13) 2.80 (1.68-4.66) C.sub.max 2.16 (1.61-2.87) 2.18
(1.55-3.04) Day 18/Day 1 AUC.sub.0-inf 2.34 (1.70-3.22) 2.25
(1.41-3.58) C.sub.max 1.82 (1.38-2.42) 1.97 (1.42-2.80) Day 22/Day
1 AUC.sub.0-inf 1.88 (1.38-2.54) 1.79 (1.11-2.88) C.sub.max 1.50
(1.13-1.99) 1.90 (1.35-2.54) Day 25/Day 1 AUC.sub.0-inf 1.30
(0.97-1.76) 1.57 (0.99-2.50) C.sub.max 1.36 (1.00-1.85) 1.72
(1.20-2.47) Day 29/Day 1 AUC.sub.0-inf 1.22 (0.92-1.62) 1.21
(0.79-1.85) C.sub.max 1.16 (0.89-1.53) 1.30 (0.94-1.82)
[0465] ECG data revealed that, on study day 30, the average change
in QTcF interval from screening values was 12.9.+-.16 milliseconds
in normal-weight subjects who completed the study and 2.6.+-.11
milliseconds in obese subjects who completed the study (Table
12).
TABLE-US-00012 TABLE 4 QTcF values relative to baseline (msec, mean
.+-. SD) Normal-weight Obese Day 1, predose 2.14 .+-. 10 7.50 .+-.
9.2 Day 1, 4 h post-dose 9.85 .+-. 12 3.83 .+-. 11 Day 15, predose
6.29 .+-. 16 2.64 .+-. 11 Day 15, 4 h post-dose 4.36 .+-. 16 -3.33
.+-. 13 Day 30 12.9 .+-. 16** 2.58 .+-. 11 **p = 0.012 compared to
baseline
[0466] Discussion. The present study evaluated the effects of
obesity on the plasma concentration of ranolazine in otherwise
healthy adults during or after cessation of posaconazole
administration. Due to the known linear correlation between
ranolazine plasma concentration and increases in the QTc interval,
the lower marketed dose of 500 mg was chosen for testing in this
study to minimize safety risks.
[0467] Without or during concomitant dosing of posaconazole, obese
and normal-weight subjects had similar C.sub.max, AUC, and t1/2
(Table 10). After cessation of posaconazole administration, both
obese and normal-weight subjects demonstrated persistence of
elevated ranolazine levels for several days. Interestingly, the
t1/2 of ranolazine increased slightly with the magnitude of the
interaction. The magnitude of the effect of posaconazole on day 15
C.sub.max was similar between normal-weight and obese subjects
(C.sub.max GMR=2.16 and 2.18, respectively). The interaction
persisted above a C.sub.max GMR of 1.5 for 7 and 10 days in
normal-weight and obese subjects, respectively. The magnitude of
the interaction on day 15 AUC was greater in normal-weight subjects
than in obese subjects (AUC GMR, day 15/day 1=3.88 and 2.90,
respectively). After day 15, however, the magnitude of the
interaction was similar in obese and normal-weight subjects and
decreased as posaconazole was eliminated from the body (FIG. 7).
The interaction between ranolazine and residual posaconazole
persisted above an AUC GMR of 1.5 for at least 7 and 10 days after
cessation of posaconazole administration in normal-weight and obese
subjects, respectively.
[0468] C.sub.max and AUC GMRs of 1.5 were also observed in
preapproval drug-drug interaction studies between ranolazine and
diltiazem, a moderate CYP3A inhibitor.
[0469] Based on the results of these preapproval studies, current
prescribing instructions for ranolazine state that the maximum
dosage of ranolazine should be limited to 500 mg twice a day when
taken concomitantly with moderate CYP3A inhibitors, and ranolazine
is contraindicated for concomitant use with strong CYP3A inhibitors
such as posaconazole. These dosing recommendations are based on the
linear correlation between ranolazine plasma concentrations and QT
interval because risk of cardiac arrhythmias increases as the QT
interval increases.
[0470] Among the 27 subjects who completed this study, an average
increase in the QTcF interval of 12.9 milliseconds was observed in
normal-weight patients on day 30 compared to screening. The average
QTcF interval in obese subjects was 2.6 milliseconds. The increase
of 12.9 milliseconds in normal subjects was statistically
significant (P=0.012) (Table 12). The changes in QTcF were observed
from safety ECG data and were not derived from a thorough QT study;
however, given current FDA guidance on QT-prolonging drugs, it is
important to note this finding.
[0471] This study is one of the first reports of a sustained
drug-drug interaction with posaconazole. Although time-dependent
inhibition of CYP3A by posaconazole is minimal, the results of
these studies suggest that inhibition of CYP3A by posaconazole
persists after cessation of administration and should be accounted
for in clinical practice.
[0472] In current clinical practice, a patient on ranolazine in
need of treatment with posaconazole would stop taking ranolazine
while being treated with posaconazole, and then resume ranolazine
shortly after finishing the posaconazole regimen to recommence
treatment for chronic angina. The results of this study suggest
that physicians should instruct their patients to delay/limit the
dose of ranolazine for an extended period after stopping
posaconazole to avoid drug-drug interactions due to residual
posaconazole levels.
[0473] Conclusion. Posaconazole, a known CYP3A strong inhibitor,
increases ranolazine concentrations to a clinically relevant and
potentially hazardous extent during concomitant administration and
for several days following its discontinuation. Although
steady-state posaconazole concentrations are lower in obese
subjects than in normal-weight subjects, its half-life is increased
in obese subjects such that the persistence of the interaction is
observed in both obese and normal-weight people. The magnitude of
the interaction between ranolazine and residual posaconazole
elevates ranolazine plasma concentrations to the extent that they
are at risk for significant QTc prolongation and potentially fatal
cardiac arrhythmias. Based on the results of this study,
administration of ranolazine should be limited to 500 mg twice
daily for 7 days after posaconazole discontinuation in patients
with BMI 18.5-24.9 kg/m.sup.2 and for 12 days in patients with
BMI.gtoreq.35 kg/m.sup.2 after ranolazine is resumed.
* * * * *