U.S. patent application number 13/301902 was filed with the patent office on 2012-03-15 for system and methods for pharmacy management of drugs.
This patent application is currently assigned to MUTUAL PHARMACEUTICAL COMPANY, INC.. Invention is credited to Matthew W. Davis.
Application Number | 20120065991 13/301902 |
Document ID | / |
Family ID | 42223370 |
Filed Date | 2012-03-15 |
United States Patent
Application |
20120065991 |
Kind Code |
A1 |
Davis; Matthew W. |
March 15, 2012 |
SYSTEM AND METHODS FOR PHARMACY MANAGEMENT OF DRUGS
Abstract
Described herein is a computer program product for pharmacy
management and its application for using drugs that are
P-glycoprotein or CYP3A4 inhibitors. Also included is a method of
using a first drug in a patient receiving a prescription for the
first drug. The computer program performs a method including
issuing a drug-drug interaction alert when a patient is receiving a
first drug and a concomitantly administered second drug.
Inventors: |
Davis; Matthew W.; (Erwinna,
PA) |
Assignee: |
MUTUAL PHARMACEUTICAL COMPANY,
INC.
Philadelphia
PA
|
Family ID: |
42223370 |
Appl. No.: |
13/301902 |
Filed: |
November 22, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12576355 |
Oct 9, 2009 |
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13301902 |
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12327258 |
Dec 3, 2008 |
7619004 |
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12576355 |
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12368700 |
Feb 10, 2009 |
7601758 |
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12327258 |
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61190053 |
Oct 15, 2008 |
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Current U.S.
Class: |
705/2 |
Current CPC
Class: |
G16H 20/13 20180101;
A61P 29/00 20180101; A61K 31/165 20130101; A61K 31/7048 20130101;
A61P 19/06 20180101; A61P 19/02 20180101; G16H 70/40 20180101; Y02A
90/10 20180101; A61K 31/165 20130101; A61K 2300/00 20130101; A61K
31/7048 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
705/2 |
International
Class: |
G06Q 50/22 20120101
G06Q050/22 |
Claims
1. A computer program product for pharmacy management, the computer
program product comprising a computer readable storage medium
having computer-readable executable instructions for: issuing a
drug-drug interaction alert when a) a first drug identifier for a
first drug is received and linked to a patient identifier so as to
indicate that the first drug is to be administered to the patient
and b) when the patient identifier is also linked to a second drug
identifier indicating that a second drug is being concomitantly
administered to the patient, wherein the drug-drug interaction
alert indicates that the second drug is being concomitantly
administered to the patient, reviewing the patient's first drug
dosing regimen prior to the first drug being dispensed, and
adjusting the patient's first drug dosing regimen responsive to the
drug-drug interaction alert, so that the first drug is to be
dispensed along with instructions for the first drug to be taken in
accordance with an adjusted first drug dosing regimen wherein the
first drug is a substrate for both CYP 3A4 and P-glycoprotein, and
wherein the second drug is a CYP3A4 or P-glycoprotein
inhibitor.
2. The computer program product of claim 1, wherein the computer
readable storage medium is non-transitory.
3. The computer program product of claim 1, wherein the drug-drug
interaction alert is issued to one or more of a pharmacy
technician, a pharmacist, or a pharmacy customer.
4. The computer program of claim 1, wherein the drug-drug
interaction alert is issued as one or both of: a written warning on
a display screen of the pharmacy management computer system, and a
printed warning attached to or packaged with the dispensed
prescription.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 12/576,355 filed Oct. 9, 2009, which is a continuation-in-part
of U.S. patent application Ser. No. 12/327,258 filed on Dec. 3,
2008, now U.S. Pat. No. 7,619,004, issued Nov. 17, 2009, and a
continuation of part of U.S. application Ser. No. 12/368,700 filed
on Feb. 10, 2009, now U.S. Pat. No. 7,601,758, issued Oct. 13,
2009, all of which claim the benefit of Provisional Patent
Application Ser. No. 61/190,053, filed Oct. 15, 2008, and all of
which are incorporated herein in their entirety.
BACKGROUND
[0002] This application relates to methods allowing for the
co-administration of colchicine together with one or more macrolide
antibiotics for therapeutic purposes with less danger than is
associated with prior methods of administration.
Colchicine:
[0003] Colchicine, chemical name
(-)-N-[(7S,12aS)-1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]he-
ptalen-7-yl]-acetamide, is a pale yellow powder soluble in water in
1:25 dilution.
[0004] Colchicine is an alkaloid found in extracts of Colchicum
autumnale, Gloriosa superba, and other plants. Among its many
biological activities, colchicine blocks microtubule polymerization
and arrests cell division. It has adversely affected
spermatogenesis in humans and in some animal species under certain
conditions.
[0005] Colchicine is a microtubule-disrupting agent used in the
treatment of gout and other conditions that may be treated,
relieved or prevented with anti-inflammatory treatment. Colchicine
impairs the motility of granulocytes and can prevent the
inflammatory phenomena that initiate an attack (or flare) of gout.
Colchicine also inhibits mitosis, thus affecting cells with high
turnover such as those in the gastrointestinal tract and bone
marrow; therefore, the primary adverse side effects include
gastrointestinal upset such as diarrhea and nausea. More serious
side effects include morbid complications such as myopathy,
neuropathy, bone marrow suppression and drug-induced cytopenia.
Particular expressions of these morbid complications may include
neuromuscular toxicity with paresthesias, pancytopenia, and
seizures.
[0006] Colchicine has a low therapeutic index. The margin between
an effective dose and a toxic dose of colchicine is much narrower
than that of most other widely used drugs. Consequently, actions
that result in increased colchicine levels in patients receiving
colchicine therapy are particularly dangerous. Co-administration of
colchicine to patients along with certain other drugs can have the
effect of increasing colchicine levels. Such drug-drug interactions
with colchicine have been reported to result in serious morbid
complications and, in some cases, death.
[0007] Colchicine is rapidly absorbed from the gastrointestinal
tract. Peak concentrations occur in 0.5 to 2 hours. The drug and
its metabolites are distributed in leukocytes, kidneys, liver,
spleen and the intestinal tract. Colchicine is metabolized in the
liver and excreted primarily in the feces with 10 to 20% eliminated
unchanged in the urine.
Gout:
[0008] Gout (or gouty arthritis) is a disease caused by a build up
of uric acid. Such a build up is typically due to an overproduction
of uric acid or to a reduced ability of the kidney to excrete uric
acid. Gout is more common in certain groups of patients, including
adult males, postmenopausal women, and hypertensives. Heavy alcohol
use, diabetes, obesity, sickle cell anemia, and kidney disease also
increase the risk of developing gout. The condition may also
develop in people who take drugs that interfere with uric acid
excretion.
[0009] In gout, crystals of monosodium urate (a salt of uric acid)
are deposited in joints, e.g., on articular cartilage, as well as
in and on tendons and surrounding tissues. These deposits correlate
with elevated concentrations of uric acid in the blood stream and
are believed to provoke the painful inflammatory reaction that
occurs in affected tissues. Gout is characterized by excruciating,
sudden, unexpected, burning pain, as well as by swelling, redness,
warmness, and stiffness in the affected joint. Low-grade fever may
also be present. The patient usually suffers from two sources of
pain. The patient experiences intense pain whenever an affected
joint is flexed. The inflammation of the tissues around the joint
also causes the skin to be swollen, tender and sore if it is even
slightly touched. For example, a blanket or even the lightest sheet
draping over the affected area could cause extreme pain.
[0010] A gout flare is a sudden attack of pain in affected joints,
especially in the lower extremities, and most commonly in the big
toe. In afflicted individuals, the frequency of gout flares
typically increases over time. In this fashion, gout progresses
from acute gout to chronic gout, which involves repeated episodes
of joint pain.
[0011] In acute gout flares, symptoms develop suddenly and usually
involve only one or a few joints. The big toe, knee, or ankle
joints are most often affected. The pain frequently starts during
the night and is often described as throbbing, crushing, or
excruciating. The joint appears infected, with signs of warmth,
redness, and tenderness. Gout flares appear substantially more
frequently with more intensive urate-lowering regimens and are a
common consequence of therapy with allopurinol. Two randomized
clinical trials assessed the efficacy of colchicine 0.6 mg twice a
day for the prophylaxis of gout flares in patients with gout
initiating treatment with urate lowering therapy. In both trials,
treatment with colchicine decreased the frequency of gout flares.
Flares of painful joints may go away in several days, but may
return from time to time. Subsequent flares usually last longer.
Acute gout may progress to chronic gout flares, or may resolve
without further attacks.
[0012] The chronic appearance of several attacks of gout yearly can
lead to joint deformity and limited joint motion. Nodular uric acid
deposits, called tophi, may eventually develop in cartilage tissue,
tendons, and soft tissues. These tophi are a hallmark of chronic
gout, which usually develop only after a patient has suffered from
the disease for many years. Deposits of monosodium urate can also
occur in the kidneys of gout sufferers, potentially leading to
chronic kidney failure.
Use of Colchicine to Treat Gout:
[0013] Colchicine can reduce pain in attacks of acute gout flares
and also can be used beneficially for treating adults for
prophylaxis of gout flares. Although its exact mode of action in
the relief of gout is not completely understood, colchicine is
known to decrease the inflammatory response to urate crystal
deposition by inhibiting migration of leukocytes, to interfere with
urate deposition by decreasing lactic acid production by
leukocytes, to interfere with kinin formation and to diminish
phagocytosis and subsequent inflammatory responses.
[0014] The anti-inflammatory effect of colchicine is relatively
selective for gouty arthritis. However, other types of arthritis
occasionally respond. It is neither an analgesic nor a uricosuric
and will not prevent progression of acute gout to chronic gout. It
does have a prophylactic, suppressive effect that helps to reduce
the incidence of acute attacks as well as to relieve the residual
pain and mild discomfort that patients with gout occasionally
experience between attacks.
Macrolide Antibiotics:
[0015] Macrolide compounds are natural products and natural product
derivatives characterized by the presence of a macrocyclic (large)
lactone ring known as a macrolide ring. The macrolide antibiotics
are important therapeutic agents. Commercially available macrolide
antibiotics include azithromycin, clarithromycin, dirithromycin,
erythromycin, and roxithromycin.
[0016] Clarithromycin is a semi-synthetic macrolide antibiotic with
in vitro activity against a variety of aerobic and anaerobic
gram-positive and gram-negative microorganisms, as well as most
Mycobacterium avium complex (MAC) microorganisms. The drug is
believed to exert its antibacterial action by binding to 50S
ribosomal subunits in susceptible microorganisms, resulting in
inhibition of protein synthesis.
[0017] Clarithromycin is indicated in the treatment of mild to
moderate infections in adults and children caused by susceptible
strains of microorganisms, such as Legionella pneumophila.
Haemophilus influenzae, Streptococcus pneumoniae and Neisseria
gonorrhoeae. Clarithromycin is also used to treat pharyngitis
(tonsillitis), sinusitis, bronchitis, community-acquired pneumonia,
uncomplicated skin infections, and disseminated mycobacterial
infections. The usual adult dose is 250 or 500 mg every 12 hours
(500 or 100 mg per day) for 7 to 14 days, taken without regard to
food.
[0018] Clarithromycin is rapidly absorbed from the gastrointestinal
tract following oral administration, with an absolute
bioavailability of approximately 50%. Peak plasma concentrations
with single doses are reached within 2 to 3 hours and steady-state
plasma concentrations are reached within 3 to 4 days. Food slightly
delays the onset of absorption and time to peak concentration and
increases the peak concentration by about 24%, but does not affect
the extent of exposure. Clarithromycin distributes readily into
body tissues and fluids and is not highly bound to plasma proteins
(65 to 75%).
Cytochrome p450 (CYP) Enzymes:
[0019] CYP enzymes are agents of drug metabolism that are found in
the liver, the gastrointestinal tract and other locations in the
body. CYP enzymes occur in a variety of closely related proteins
referred to as isozymes. Some of these that have been identified as
important in drug metabolism are CYP1A2, CYP2A6, CYP2B6, CYP2C8,
CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Different CYP
isozymes may preferentially metabolize different drugs. For
example, phenyloin and fosphenyloin have been reported to be
preferentially metabolized by CYP2C9, CYP2C19, and CYP3A4, while
CYP2D6 has been reported to be responsible for the metabolism of
many psychotherapeutic agents, such as thioridazine.
CYP Isozymes and Drug-Drug Interactions:
[0020] Examples of CYP-mediated drug-drug interactions include
those involving CYP1A2 and CYP2E1 isozymes, which have been
reported to be involved in drug-drug interactions involving
theophylline, and those involving CYP2C9, CYP1A2, and CYP2C19,
which have been reported to be involved in drug-drug interactions
involving warfarin.
[0021] The 3A family of CYP isozymes, particularly CYP3A4, is also
known to be involved in many clinically significant drug-drug
interactions, including those involving colchicine and macrolide
antibiotics, as well as those involving non-sedating antihistamines
and cisapride. CYP3A5 shares very similar protein structure,
function and substrate specificity with CYP3A4. The CYP3A5*3 allele
is a gene variant that does not express CYP3A5 enzyme. As a result
of this genetic variation, about half of African-American subjects
and 70-90% of Caucasian subjects do not express CYP3A5, while
expression is more common in other ethnic groups.
[0022] While drugs are often targets of CYP-mediated metabolism,
some may also alter the expression and activity of such enzymes,
thus impacting the metabolism of other drugs.
[0023] Colchicine is both a target of and a modulator of CYP
isozymes. The biotransformation of colchicine in human liver
microsomes involves formation of 3-demethylchochicine and
2-demethylcolchicine. As shown by experiments using antibodies
against CYP3A4 and experiments using chemical inhibition of CYP3A4,
this transformation is correlated with (and thus apparently
mediated by) CYP3A4 activity. CYP2A6, CYP2C9, CYP2C19, CYP2D6, and
CYP2E1 do not appear to catalyze this biotransformation.
[0024] Studies on the effect of colchicine on expression of
selected CYP isozymes in primary cultures of human hepatocytes have
been reported. Dvorak et al. (Acta Univ. Palacki. Olomuc., Fac.
Med. (2000) 143:47-50) provided preliminary data on the effect of
colchicine and several of its derivatives on protein levels of
CYP1A2, CYP2A6, CYP2C9/19, CYP2E1, and CYP3A4 as assessed by
immunoblotting. Colchicine caused an increase in CYP2E1 protein
levels and appeared to decrease protein levels of CYP1A2,
CYP2C9/19, and CYP3A4, with 10 .mu.M colchicine causing a greater
reduction in each isozyme than 1 .mu.M colchicine. The
3-demethylchochicine metabolite was reported to cause a decrease in
protein for CYP1A2, CYP2C9/19, CYP2E1, and CYP3A4. The levels of
CYP2A6 appeared unaffected by colchicine or any of the tested
metabolites. In a more complete report on expression of CYP1A2,
CYP2A6, CYP2C9, CYP2C19, CYP2E1, and CYP3A4, Dvorak et al.
(Toxicology in Vitro (2002) 16:219-227) concluded that CYP1A2
protein content in 1 .mu.M colchicine treated cells was not
different from that in control cells, while the inducer TCDD
increased the level of CYP1A2 protein by an average of three-fold.
The levels of CYP2A6 protein were apparently unaffected by
colchicine, while enzyme activities of CYP3A4 and CYP2C9 were
significantly decreased by colchicine and activity of CYP2E1 was
not affected. Northern blots showed that colchicine suppressed
CYP2C9 mRNA levels by about 20% and did not alter CYP3A4 mRNA
levels as compared to control cells. A subsequent study by Dvorak
et al. (Mol. Pharmacol. (2003) 64:160-169) showed that colchicine
decreased both basal and rifampicin-inducible and
phenobarbital-inducible expression of CYP2B6, CYP2C8/9, and
CYP3A4.
[0025] Like colchicine, clarithromycin is a target of metabolism by
CYP3A isozymes. In non-fasting healthy human subjects, the
elimination half-life of clarithromycin is about 3 to 4 hours with
250 mg administered every 12 hours, but increases to 5 to 7 hours
with 500 mg administered every 8 to 12 hours. Approximately 20% and
30% of the dose, respectively, is excreted as unchanged drug in
urine following oral administration of 250 and 500 mg
clarithromycin given every 12 hours. Approximately 10 to 15% of the
dose is excreted in urine as 14-hydroxyclarithromycin, an active
metabolite of clarithromycin with substantial antibacterial
activity. About 40% of an oral clarithromycin dose is excreted in
feces.
[0026] Clarithromycin is also a potent inhibitor of CYP3A isozymes,
as are other macrolide antibiotics. This inhibition is not rapidly
reversible. Due to the limited reversibility of the inhibition of
CYP3A isozymes by clarithromycin, CYP3A activity may not return to
normal after a course of treatment with clarithromycin until the
body produces adequate amounts of CYP3A isozymes to replace those
irreversibly inhibited by the clarithromycin. Thus, it may take one
to two weeks for CYP3A metabolic activity to return to normal
following treatment with clarithromycin or other macrolide
antibiotics.
[0027] P-glycoprotein (Pgp) is an ATP-dependent cell surface
transporter molecule. Pgp actively pumps certain compounds, notably
including drugs such as colchicine, out of cells. Pgp is encoded by
the Adenosine triphosphate-binding cassette subfamily B member 1
(ABCB1) gene, also referred to as the multiple drug resistance 1
gene (MDR1).
[0028] Clarithromycin is an inhibitor of Pgp, as are other
macrolide antibiotics. In vitro, agents that inhibit CYP 3A4
typically also inhibit Pgp, and the magnitude of Pgp inhibition in
vitro generally trends proportionally with magnitude of CYP 3A4
inhibition. However, equipotent CYP 3A4 inhibitors can exhibit
different degrees of Pgp inhibition.
[0029] Thus clarithromycin and other macrolide antibiotics, in
addition to inhibiting the metabolic breakdown of colchicine by
inhibiting CYP 3A4 isozymes, can block a mechanism by which
colchicine is pumped out of cells. Both the inhibition of
colchicine breakdown by CYP 3A4 and the inhibition of the pumping
of colchicine out of cells by Pgp have the effect of increasing the
intracellular levels of colchicine.
[0030] Since colchicine acts intracellularly, the combined effects
of CYP 3A4 inhibition and Pgp inhibition by clarithromycin (and
related macrolide antibiotics) can cause colchicine toxicity in
patients taking what would be a safe dose of colchicine in the
absence of concomitant macrolide antibiotic administration.
[0031] Drug-drug interactions, such as the enhancement of
colchicine toxicity by macrolide antibiotics, present a health risk
to patients and a medical challenge for all medical care workers.
Various studies of adverse reactions from exposure to multiple
drugs have found that 6.5-23% of the adverse reactions result from
drug-drug interactions. Unfortunately, each year a number of deaths
occur as the direct result of patients adding a concomitant
prescription pharmaceutical product to their existing medication
regimen.
[0032] With regard to co-administration of colchicine with
clarithromycin and other macrolide antibiotics, warnings have
recently been published urging caution, or arguing that the two
drugs should not be co-administered. For example, on Jul. 5, 2006
the US Food and Drug Administration (the FDA) approved safety
labeling changes for clarithromycin tablets, extended-release
tablets, and oral suspension to warn of the risk for increased
exposure to colchicine in patients receiving both drugs. The
Warnings section of the prescribing information for clarithromycin
now includes the following statement: "There have been
post-marketing reports of colchicine toxicity with concomitant use
of clarithromycin and colchicine, especially in the elderly, some
of which occurred in patients with renal insufficiency. Deaths have
been reported in some such patients." In addition, the following
was added to the Precautions section of the prescribing
information: "[c]olchicine is a substrate for both CYP3A and the
efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other
macrolides are known to inhibit CYP3A and Pgp. When clarithromycin
and colchicine are administered together, inhibition of Pgp and/or
CYP3A by clarithromycin may lead to increased exposure to
colchicine. Patients should be monitored for clinical symptoms of
colchicine toxicity."
[0033] A 2006 report entitled "Life-threatening Colchicine Drug
Interactions" cautioned that "[c]olchicine should not be used with
clarithromycin or erythromycin, and given the potential for fatal
outcomes, it would be prudent to avoid all PGP inhibitors with
colchicine" (Horn, J. R. and Hansten, P. D., Pharmacy Times, May
2006, p. 111).
[0034] More recently, a publication in May, 2008 ended with the
conclusion that "[t]he combined prescription of clarithromycin or
other CYP3A4 inhibitors and colchicine should be avoided." Van der
Velden, et al., (Neth. J. Med. 2008 May; 66(5):204-6).
[0035] There accordingly remains a need in the art for improved
methods for administering colchicine to patients who are
concomitantly being treated with macrolide antibiotics so as to
reduce the occurrence of dangerous colchicine toxicity. The present
disclosure addresses this need and provides further advantages.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1 shows mean colchicine plasma concentrations following
administration of single and multiple oral doses of colchicine 0.6
mg in healthy adults, N=13, Y axis=colchicine concentration, ng/mL,
X axis=time in hours, .diamond-solid.=day 1, .quadrature.=day 25.
See Example 1.
[0037] FIG. 2 shows a pharmacokinetic profile comparison of
single-dose colchicine (0.6 mg, alone) and single-dose colchicine
(0.6 mg) co-administered with steady-state clarithromycin in
healthy adults, Y axis=colchicine concentration, ng/mL, X axis=time
in hours, N=23, =day 1, .diamond-solid.=day 29. See Example 2.
SUMMARY
[0038] Disclosed herein are methods for more safely administering
colchicine concomitantly with administration of macrolide
antibiotics such as clarithromycin or erythromycin. It has now been
discovered that certain reduced or limited colchicine dosages, when
administered with concomitantly administered recommended dosage
amounts of macrolide antibiotics, certain "colchicine plus
macrolide" dosing regimens, achieve plasma colchicine levels that
are therapeutically effective, but are not significantly higher,
and therefore not significantly more toxic, than plasma levels
achieved by administration of manufacturers' recommended colchicine
dosage amounts in the absence of concomitant macrolide antibiotic
administration. Thus, in spite of recent published warnings that
the two should not be concomitantly administered, colchicine and
macrolide antibiotics can be administered concomitantly without
undue hazard when colchicine is administered as disclosed
herein.
[0039] In one embodiment, colchicine treatment is administered to a
patient in suffering from a condition treatable with colchicine,
and the patient is concomitantly receiving administration of a
macrolide antibiotic to treat an infection. The colchicine therapy
may involve either palliative or prophylactic treatment, or
both.
[0040] In one embodiment, colchicine is employed in the prophylaxis
of gout flares in a human individual, that is, to prevent gout
flares. Such treatment can also be referred to as chronic
treatment, meaning long-term treatment to reduce the occurrence of
gout flares. In one embodiment, the method comprises determining a
first colchicine dosage amount adapted for daily oral
administration to the gout patient to prevent gout flares in the
absence of concomitant administration of clarithromycin or
erythromycin, determining a second colchicine dosage amount that is
a 50% to 75% reduction of the first colchicine dosage amount, and
orally administering the second colchicine dosage amount to the
gout patient who is concomitantly receiving administration of
clarithromycin or erythromycin. The second colchicine dosage amount
is administered to the patient in one or more doses one or more
times per day every day, or double the second colchicine dosage
amount is administered to the patient in one or more doses per day
every other day.
[0041] In certain embodiments, in this method, the 50% to 75%
reduction comprises one or more of 1) reducing the number of doses
of colchicine administered per day, 2) reducing the amount of
colchicine administered per dose, and 3) reducing the
administration of colchicine from administration every day to
administration every other day. For example, in this method, the
50% to 75% reduction may comprise reducing both the number of doses
of colchicine administered per day and the amount of colchicine
administered per dose.
[0042] In other aspects of these embodiments, one or more (where
not mutually exclusive) of the following applies: 1) the patient is
administered each dose of colchicine as one 0.6 mg colchicine
tablet or as one half of a 0.6 mg colchicine tablet, 2) the patient
is an adult, 3) the adult patient is less than 70 years old, 4) the
patient is receiving concomitant administration of clarithromycin,
6) the second colchicine dosage amount is a one-half reduction of
the first colchicine dosage amount, 7) the second colchicine dosage
amount is a two-thirds reduction of the first colchicine dosage
amount, 8) the second colchicine dosage amount is a three-quarters
reduction of the first colchicine dosage amount, 9) the first
colchicine dosage amount is about 1.2 mg per day and the second
colchicine dosage amount is about 0.3 mg per day, 10) the first
colchicine dosage amount is about 0.6 mg per day and the second
colchicine dosage amount is about 0.15 mg per day.
[0043] In aspects of these embodiments, the second colchicine
dosage amount of about 0.3 mg per day is administered as one half
of a 0.6 mg colchicine tablet once a day every day, and the second
colchicine dosage amount of about 0.15 mg per day is administered
as one half of a 0.6 mg colchicine tablet once a day every other
day.
[0044] In one embodiment, a method of using colchicine for
prophylactic treatment of gout flares in a human gout patient so as
to reduce the occurrence of colchicine toxicity when said patient
is receiving concomitant administration of clarithromycin or
erythromycin, comprises: orally administering a second colchicine
daily dosage amount for prophylactic treatment of gout flares to
the human gout patient who is concomitantly receiving
administration of clarithromycin or erythromycin, wherein the
second colchicine daily dosage amount is a 50 to 75% reduction of a
first colchicine daily dosage amount suitable for daily oral
administration for the prophylactic treatment of gout flares in the
absence of concomitant administration of clarithromycin or
erythromycin, wherein concomitant administration of clarithromycin
or erythromycin is administration within 1 to 2 days of orally
administering the second colchicine dosage amount, and wherein the
first colchicine daily dosage amount is 1.2 mg administered as two
0.6 mg doses per day, or the first colchicine daily dosage amount
is 0.6 mg per day.
[0045] In another embodiment, a method of using colchicine for
prophylactic treatment of gout flares in a human gout patient so as
to reduce the occurrence of colchicine toxicity when said patient
is receiving concomitant administration of clarithromycin or
erythromycin, comprises: orally administering a second colchicine
daily dosage amount for prophylactic treatment of gout flares to
the human gout patient who is concomitantly receiving
administration of clarithromycin or erythromycin, wherein the
second colchicine daily dosage amount is a 75% reduction of a first
colchicine daily dosage amount suitable for daily oral
administration for the prophylactic treatment of gout flares in the
absence of concomitant administration of clarithromycin or
erythromycin, wherein concomitant administration of clarithromycin
or erythromycin is administration within 1 to 2 days of orally
administering the second colchicine dosage amount. In certain
embodiments, the first colchicine daily dosage amount is 1.2 mg
administered as two 0.6 mg doses per day, or the first colchicine
daily dosage amount is 0.6 mg per day.
[0046] In another embodiment, a method of using colchicine for
prophylactic treatment of gout flares in an adult human gout
patient so as to reduce the occurrence of colchicine toxicity when
said patient is receiving concomitant administration of
clarithromycin or erythromycin comprises administering a reduced
colchicine daily dosage amount to the patient for prophylactic
treatment of gout flares, wherein the reduced colchicine daily
dosage amount is 50-75% of a manufacturers' recommended colchicine
daily dosage amount for the prophylactic treatment of gout flares
in the absence of concomitant clarithromycin or erythromycin
administration, wherein concomitant administration of
clarithromycin or erythromycin is administration within 1 to 2 days
of orally administering the second colchicine dosage amount. In
certain embodiments, the manufacturers' recommended colchicine
daily dosage amount for the prophylactic treatment of gout flares
in the absence of concomitant clarithromycin or erythromycin
administration is 1.2 mg/day or 0.6 mg/day.
[0047] In another embodiment, a method of using colchicine for
prophylactic treatment of gout flares in an adult human gout
patient so as to reduce the occurrence of colchicine toxicity when
said patient is receiving concomitant administration of
clarithromycin or erythromycin comprises administering a reduced
colchicine daily dosage amount to the patient for prophylactic
treatment of gout flares, wherein the reduced colchicine daily
dosage amount is 75% of a manufacturers' recommended colchicine
daily dosage amount for the prophylactic treatment of gout flares
in the absence of concomitant clarithromycin or erythromycin
administration, wherein concomitant administration of
clarithromycin or erythromycin is administration within 1 to 2 days
of orally administering the second colchicine dosage amount.
[0048] In one embodiment, the daily colchicine is coadministered
with a urate-lowering drug such as febuxostat or allopurinol. Daily
dosage amounts of febuxostat are typically 40 mg or 80 mg once
daily. Daily dosage amounts of allopurinol are 200 to 300 mg per
day for patients with mild gout and 400 to 600 mg per day for those
with moderately severe tophaceous gout. The appropriate dosage
amount may be administered in divided doses or as a single
equivalent dose with the 300 mg tablet. Dosage requirements in
excess of 300 mg should be administered in divided doses. The
minimal effective dosage amount is 100 to 200 mg daily and the
maximal recommended dosage amount is 800 mg daily. To reduce the
possibility of flare-up of acute gouty attacks, it is recommended
that the patient start with a low dosage amount of allopurinol (100
mg daily) and increase at weekly intervals by 100 mg until a serum
uric acid level of 6 mg/dL or less is attained but without
exceeding the maximal recommended dosage amount.
[0049] In yet another embodiment, a method of using colchicine for
prophylactic treatment of gout flares in a human gout patient that
is also receiving treatment with urate-lowering therapy so as to
reduce the occurrence of colchicine toxicity when said patient is
receiving concomitant administration of clarithromycin or
erythromycin, comprises: orally administering a second colchicine
daily dosage amount for prophylactic treatment of gout flares to
the human gout patient who is concomitantly receiving
administration of clarithromycin or erythromycin, wherein the
second colchicine daily dosage amount is a 75% reduction of a first
colchicine daily dosage amount suitable for daily oral
administration for the prophylactic treatment of gout flares in the
absence of concomitant administration of clarithromycin or
erythromycin, wherein concomitant administration of clarithromycin
or erythromycin is administration within 1 to 2 days of orally
administering the second colchicine dosage amount. In certain
embodiments, the first colchicine daily dosage amount is 1.2 mg
administered as two 0.6 mg doses per day, or the first colchicine
daily dosage amount is 0.6 mg per day. In certain embodiments, the
urate lowering therapy is allopurinol or febuxostat.
[0050] In another embodiment, colchicine is used for the treatment
of acute gout, that is, treatment of gout flares. In one
embodiment, the method comprises determining a first colchicine
dosage amount adapted for oral administration to the gout patient
to treat gout flares in the absence of concomitant administration
of clarithromycin or erythromycin, determining a second colchicine
dosage amount that is a 50% to 75% reduction, preferably a
two-thirds or three quarters reduction, of the first colchicine
dosage amount, and orally administering the second colchicine
dosage amount to the gout patient who is concomitantly receiving
administration of clarithromycin or erythromycin. In one
embodiment, the colchicine administration is not repeated for at
least three days.
[0051] In certain embodiments, the 50% to 75% reduction comprises
one or more of 1) reducing the number of doses of colchicine
administered (e.g., per day), 2) reducing the amount of colchicine
administered per dose (i.e., reducing the size of at least one
colchicine dose), and 3) reducing the administration of colchicine
from administration every day to administration every other day.
For example, in this method, the 50% to 75% reduction may comprise
reducing both the number of doses of colchicine administered per
day and the amount of colchicine administered per dose. In one
embodiment, the colchicine administration is not repeated for at
least three days.
[0052] In other aspects of these embodiments, one or more (where
not mutually exclusive) of the following apply: 1) the patient is
administered each dose of colchicine as one 0.6 mg colchicine
tablet or as one half of a 0.6 mg colchicine tablet (e.g. one half
a scored 0.6 mg colchicine tablet), 2) the patient is an adult, 3)
the adult patient is less than 70 years old, 4) the patient is
receiving concomitant administration of clarithromycin, 5) the
second colchicine dosage amount is about a one-half reduction of
the first colchicine dosage amount, 6) the second colchicine dosage
amount is about a two-thirds reduction of the first colchicine
dosage amount, 7) the second colchicine dosage amount is about a
three-quarters reduction of the first colchicine dosage amount, 8)
the first colchicine dosage amount is about 1.8 mg per day and the
second colchicine dosage amount is about 0.6 mg per day, 9) the
second colchicine dosage amount is a single dose of about 0.6 mg,
and after administration of the single dose ingestion of colchicine
is stopped until a subsequent gout flare occurs, 10) the second
colchicine dosage amount is a single dose of about 0.6 mg of
colchicine, and after administration of the single dose ingestion
of colchicine is not repeated within a 3-day period
[0053] In an additional embodiment, the first colchicine dosage
amount is about 1.8 mg per day and the second colchicine dosage
amount is a single 0.6 mg dose, and preferably ingestion of
colchicine is not repeated for at least three days after the single
dose is administered.
[0054] In another embodiment, a method of using colchicine to treat
a gout flare in a human patient who is receiving concomitant
administration of clarithromycin or erythromycin comprises
determining a first colchicine dosage amount adapted for oral
administration to the patient to treat a gout flare in the absence
of concomitant administration of clarithromycin or erythromycin,
determining a second colchicine dosage amount that is a 50-75%
reduction of the first colchicine dosage amount, and orally
administering the second colchicine dosage amount to the patient
who is experiencing a gout flare and is concomitantly receiving
administration of clarithromycin or erythromycin, wherein
concomitant administration of clarithromycin or erythromycin is
administration within 1 to 2 days of orally administering the
second colchicine dosage amount, and not repeating colchicine
administration for at least three days.
[0055] In another embodiment, a method of using colchicine to treat
a gout flare in a human patient who is receiving concomitant
administration of clarithromycin or erythromycin comprises
determining a first colchicine dosage amount adapted for oral
administration to the patient to treat a gout flare in the absence
of concomitant administration of clarithromycin or erythromycin,
determining a second colchicine dosage amount that is about a two
thirds reduction of the first colchicine dosage amount, and orally
administering the second colchicine dosage amount to the patient
who is experiencing a gout flare and is concomitantly receiving
administration of clarithromycin or erythromycin, wherein
concomitant administration of clarithromycin or erythromycin is
administration within 1 to 2 days of orally administering the
second colchicine dosage amount, and not repeating colchicine
administration for at least three days.
[0056] In another embodiment, a method of using colchicine to treat
a gout flare in an adult human gout patient so as to reduce the
occurrence of colchicine toxicity when said patient is receiving
concomitant administration of clarithromycin or erythromycin
comprises administering a reduced colchicine dosage amount to the
patient to treat gout flares, wherein the reduced colchicine dosage
amount is about 50% to about 75% of a manufacturer's recommended
colchicine dosage amount in the absence of concomitant
clarithromycin or erythromycin administration, and not repeating
colchicine administration for at least three days, wherein
concomitant administration of clarithromycin or erythromycin is
administration within 1 to 2 days of orally administering the
second colchicine dosage amount.
[0057] In a one embodiment, the patient is administered the
colchicine according to a colchicine dosing regimen of a single
starting colchicine dose of no more than about 0.6 mg colchicine,
followed by either no additional colchicine doses within about 12,
24, 48, or 72 hours, or followed by at least one additional
colchicine dose within 12 hours and no more frequently than once
every hour (e.g., every 3, 4, 6, 8, or 12 hours). In this
embodiment, each additional colchicine dose is no greater than
about 0.3 mg and the patient may be an adult patient or a pediatric
patient. In one embodiment, the starting colchicine dose is about
0.6 mg or about 0.3 mg, and each additional colchicine dose is
about 0.3 mg. When additional doses are administered, it is
preferred that only two, three, or four additional colchicine doses
are administered within about 24 hours. In another embodiment, the
patient is an adult patient and the starting colchicine dose is
about 0.6 mg and each additional colchicine dose, if any, is about
0.3 mg. In one embodiment only three additional colchicine doses
are administered within about 24 hours.
[0058] In another embodiment, colchicine is administered to a
patient suffering from a condition treatable with colchicine, and
the concomitant macrolide antibiotic is administered concurrently,
or the patient has recently completed a dosing regimen of a
macrolide antibiotic to treat an infection, and the patient is
(immediately or within a period of two weeks, preferably three
days, more preferably within 48 hours or 24 hours after completion
of the macrolide antibiotic dosing regimen) administered a single
dose of no more than about 0.6 mg of colchicine, preferably 0.3 mg
or 0.6 mg of colchicine. For example, the starting colchicine dose
is about 0.6 mg and only one additional colchicine dose is
administered within about 24 hours and the additional colchicine
dose is about 0.6 mg.
[0059] A preferred antibiotic for use in the disclosed methods is
one that is an inhibitor of either or both of CYP3A and
P-glycoprotein, preferably both. In certain embodiments, the
antibiotic is dirithromycin, erythromycin, roxithromycin, or more
preferably, clarithromycin or erythromycin. The clarithromycin may
be administered to the patient at a dosage amount of about 500 mg
daily and the colchicine dosing regimen is one about 0.6 mg
colchicine dose to start, followed by 0, 1, 2, 3, or 4 additional
colchicine doses of about 0.6 mg every 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, or 12 hours (e.g., every 2, 3, 4, 5, or 6 hours) after the
preceding colchicine dose. Alternately, the clarithromycin may be
administered to the patient at a dosage amount of about 1000 mg
daily and the colchicine dosing regimen is one about 0.3 mg
colchicine dose to start, followed by 0, 1, 2, 3, or 4 additional
colchicine doses of about 0.3 mg each every 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, or 12 hours (e.g., every 3, 4, 5, or 6 hours) after the
preceding colchicine dose. In a preferred regimen for treatment of
acute gout flares, ingestion of colchicine is continued until a
total of no more than about 1.2, 1.4, 1.6, 1.8, 2, or 2.4 mg of
colchicine has been ingested, after which ingestion of colchicine
is stopped until a subsequent acute gout flare occurs. In still
another preferred regimen, clarithromycin may be administered to a
patient, e.g., at a dosage amount of about 250 mg B.I.D. for a
period of about 7 to 10 days, and the colchicine dosing regimen is
administered to the patient upon completion of the clarithromycin
dosing regimen, wherein the colchicine dosing regimen consists of
the administration of no more than one dose of no more than 0.6 mg
of colchicine. In one embodiment, the colchicine is administered as
a dosage form of 0.6 mg (e.g., one 0.6 mg colchicine tablet), or
0.3 mg (e.g., one half of a 0.6 mg tablet) of colchicine and
administration of the dosage form is not repeated within a period
of at least about two days, preferably at least about three
days.
[0060] In these and other embodiments, the colchicine-responsive
condition is gout (e.g. a gout flare in a chronic gout sufferer),
familial Mediterranean fever (FMF), thrombocytopenic purpura,
pericarditis, scleroderma, or Behcet's disease. The gout may be an
acute gout flare or chronic gout. For gout, the dosing regimen is
generally continued until a total of no more than 2.4 mg of
colchicine has been ingested, after which ingestion of colchicine
is stopped until a subsequent gout flare occurs.
[0061] Another embodiment comprises administering colchicine to a
patient also taking clarithromycin, or having completed treatment
with clarithromycin within the prior 14 days, the patient being
administered a single dosage amount of about 0.6 mg or about 0.3 mg
of colchicine to treat a gout flare, which administration is not
repeated within any 3-day period.
[0062] In another aspect, herein disclosed is a method for
increasing the blood plasma levels of colchicine in a patient to
whom colchicine is being administered to treat or prevent a
colchicine-responsive condition. This method comprises the
concomitant dosing of the patient with a sufficient amount of a
macrolide antibiotic to increase the C.sub.max of colchicine by
about 167% to 200%, or to increase the AUC of colchicine in the
patient by about 240% to 250%, or to increase the plasma half-life
of colchicine by about 233%, or to decrease the clearance of
colchicine by about 75%, compared to the C.sub.max, AUC, plasma
half-life, or clearance in the same or a matched patient when not
being administered a concomitant macrolide antibiotic. In a one
embodiment, the patient is being administered no more than three
hourly doses of about 0.6 mg of colchicine or less, the macrolide
antibiotic is clarithromycin, and the amount of macrolide
antibiotic is from about 500 mg to about 1000 mg, with about 500 mg
being preferred.
[0063] In another aspect, herein disclosed are methods for using
colchicine which methods involve the use of pharmacy management
systems.
[0064] In one aspect one such method comprises a pharmacy receiving
a prescription for colchicine for a patient who is suffering from
gout (e.g., acute gout flares or chronic gout) and who is
concomitantly being treated with a macrolide antibiotic that is an
inhibitor of CYP3A and P-glycoprotein, followed by the pharmacy
dispensing colchicine in response to receipt of the prescription,
wherein the dispensing is preceded by entry into a first computer
readable storage medium, in functional communication with a
computer, of a unique patient identifier for said patient and at
least one drug identifier for colchicine linked to the patient
identifier so as to indicate that colchicine is to be administered
to the patient. The computer is programmed to issue a drug-drug
interaction alert when the at least one drug identifier for
colchicine is entered linked to the patient identifier so as to
indicate that colchicine is to be administered to the patient and
when the patient identifier is also linked to an identifier
indicating that a macrolide antibiotic that is an inhibitor of
CYP3A or P-glycoprotein is being concomitantly administered to the
patient. Upon entry of the at least one drug identifier for
colchicine linked to the patient identifier, a drug-drug
interaction alert is issued to one or more of a pharmacy
technician, a pharmacist, or a pharmacy customer obtaining the
colchicine, said alert indicating that a macrolide antibiotic is
being concomitantly administered to the patient and that prior to
the colchicine being dispensed, the colchicine dosing regimen must
be reviewed and, if necessary adjusted, so that when the colchicine
is delivered to the pharmacy customer obtaining the colchicine it
is delivered along with instructions for the colchicine to be taken
in accordance with a dosing regimen of no more than one about 0.6
mg colchicine dose to start (e.g., following the onset of the acute
gout attack or the first sign of a gout flare) followed by either:
no additional colchicine doses within about 12, 24, 48, or 72
hours, or at least one additional colchicine dose within about 12
hours and no more frequently than once every hour and wherein each
additional colchicine dose is no greater than about 0.6 mg, and
wherein the patient ingests the colchicine as instructed.
[0065] The drug-drug interaction alert may be issued as one or both
of a written warning on a display screen of the pharmacy management
computer system, and a printed warning. The printed warning may be
attached to or packaged with the dispensed prescription.
[0066] In one aspect, the identifier indicating that a macrolide
antibiotic is being concomitantly administered to the patient is an
identifier indicating that the macrolide antibiotic is
clarithromycin and is linked to at least one further identifier
indicating that the clarithromycin is prescribed so that 500 mg of
clarithromycin is to be ingested by the patient daily, in which
case the dosing regimen for colchicine is preferably one about 0.6
mg colchicine dose to start, optionally followed by additional
colchicine doses, e.g., 0, 1, 2, 3, or 4 additional colchicine
doses within 24 hours of about 0.3 mg ingested every 1, 2, 3, 4, 5,
6, 7, 8, 9 10, 11, or 12 hours (e.g., every 2, 3, 4, 5, or 6 hours)
after the preceding colchicine dose. In another embodiment, the
identifier indicating that a macrolide antibiotic is being
concomitantly administered to the patient is an identifier
indicating that the macrolide antibiotic is clarithromycin is
linked to at least one further identifier, entered into a second
computer readable storage medium in functional communication with a
computer, the second storage medium being the same as or different
from the first storage medium, and the further identifier
indicating that the clarithromycin is prescribed so that about 500
mg of clarithromycin is to be ingested by the patient daily, in
which case the colchicine dosing regimen is (preferably) one about
0.6 mg colchicine dose to start, followed by an about 0.3 mg
colchicine dose ingested every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
or 12 hours (e.g., every six to eight hours) after the preceding
colchicine dose.
[0067] In yet another aspect, the identifier indicating that a
macrolide antibiotic is being concomitantly administered to the
patient is an identifier indicating that the macrolide antibiotic
is clarithromycin and is linked to at least one further identifier,
entered into a second computer readable storage medium in
functional communication with a computer, the second storage medium
being the same as or different from the first storage medium, and
the further identifier indicating that the clarithromycin is
prescribed so that about 1000 mg of clarithromycin is to be
ingested by the patient daily and the dosing regimen is one about
0.3 mg colchicine dose to start, followed by an about 0.3 mg
colchicine dose ingested every 2, 3, 4, 5, 6, 7, or 8 hours (e.g.,
every eight to twelve hours) after the preceding colchicine
dose.
[0068] One dosing regimen calls for ingestion of colchicine to be
continued until a total of no more than 1.2 mg or 2.4 mg of
colchicine has been ingested, after which ingestion of colchicine
is to be stopped, e.g., for at least 2, 3, 4, 5, 6, or 7 days, or
until a subsequent acute gout flare, or the first sign of a
subsequent gout flare, occurs.
[0069] Also disclosed herein is a dosage amount adjustment method
for administering colchicine to a patient to treat a medical
condition, the patient concomitantly suffering from an infection
amenable to treatment with a macrolide antibiotic. The method
comprises determining a first, a second, and a subsequent
monotherapy colchicine dosage amount and a colchicine treatment
schedule; and determining an antibiotic dosage amount and an
antibiotic treatment schedule; and administering the macrolide
antibiotic to the patient at the antibiotic dosage amount according
to the antibiotic treatment schedule while concomitantly
administering colchicine to the patient according to the colchicine
treatment schedule at a first, a second, and a subsequent
polytherapy colchicine dosage amount, each of which is a fraction
of each of the corresponding first, second, and subsequent
monotherapy colchicine dosage amounts, the fraction being less than
or equal to about 2/3.
[0070] An alternate embodiment of this method comprises determining
a monotherapy colchicine dosage amount and a colchicine treatment
schedule, each adapted so that, when colchicine is administered to
the patient in the absence of concomitant administration of the
antibiotic at the monotherapy colchicine dosage amount according to
the colchicine treatment schedule, a therapeutic circulating plasma
level of colchicine is predicted to be achieved in the patient that
is safe and effective to treat the condition in the patient while
posing an acceptable adverse effect risk; and determining an
antibiotic dose and an antibiotic treatment schedule, each adapted
so that, when the antibiotic is administered to the patient at the
antibiotic dosage amount according to the antibiotic treatment
schedule, a circulating level of the antibiotic is predicted to be
achieved in the patient that is safe and therapeutically effective
to treat the infection in the patient and administering the
antibiotic to the patient at the antibiotic dosage amount according
to the antibiotic treatment schedule while concomitantly
administering colchicine to the patient at a polytherapy colchicine
dosage amount that is a fraction less than or equal to 1/2 of the
monotherapy colchicine dosage amount to the patient according to
the colchicine treatment schedule.
[0071] According to this embodiment, upon the administering of the
antibiotic to the patient at the antibiotic dosage amount according
to the antibiotic treatment schedule while concomitantly
administering colchicine to the patient at the polytherapy
colchicine dose according to the colchicine treatment schedule, the
therapeutic circulating level of colchicine is achieved in the
patient. Preferably, the fraction is selected from 1/12, 1/6, 1/4,
1/3, 5/12, and 1/2, more preferably, the fraction is 1/3 or 1/2.
Preferably the antibiotic is selected from clarithromycin,
dirithromycin, erythromycin and roxithromycin. Exemplary conditions
are selected from gout, FMF, thrombocytopenic purpura, and Behcet's
disease. In a preferred embodiment, the gout is an acute gout flare
and the colchicine treatment schedule is an acute treatment
schedule adapted for treatment of acute gout flares, or the gout is
chronic gout, and the colchicine treatment schedule is a chronic
treatment schedule adapted for prophylaxis of flares. In another
embodiment, the fraction is 1/3 or 1/2 and treatment with
colchicine is initiated subsequent to initiation of treatment with
clarithromycin.
[0072] In one embodiment, each of the monotherapy colchicine doses
and the colchicine treatment schedule are each adapted so that,
when colchicine is administered to the patient at the monotherapy
colchicine dose according to the colchicine treatment schedule in
the absence of concomitant administration of the antibiotic, a
therapeutic circulating level of colchicine is predicted to be
achieved in the patient that is predicted to be safe and effective
to treat the condition in the patient while posing an acceptable
adverse effect risk.
[0073] Alternately, the antibiotic dose and the antibiotic
treatment schedule are each adapted so that, when the antibiotic is
administered to the patient at the antibiotic dose according to the
antibiotic treatment schedule a circulating level of the antibiotic
is predicted to be achieved in the patient that is therapeutically
effective to treat the infection in the patient.
[0074] In one embodiment, upon the administration of the antibiotic
to the patient at the antibiotic dose according to the antibiotic
treatment schedule while concomitantly administering colchicine to
the patient according to the colchicine treatment schedule at the
polytherapy colchicine dose, a therapeutic circulating level of
colchicine is predicted to be achieved in the patient that is
predicted to be safe and effective to treat the condition in the
patient while posing an acceptable adverse effect risk In one
embodiment, each subsequent colchicine dose is the same as the
second colchicine dose. In another embodiment, each of the second
and subsequent colchicine doses are the same as the first
colchicine dosage amounts. In another, the fraction is selected
from about 1/12, about 1/6, about 1/4, about 1/3, about 5/12, about
1/2, and about 7/12, e.g., about 1/2 or about 2/3. In certain
embodiments, the colchicine treatment schedule is once-a-day,
twice-a-day, three-times-a-day or four-times-a-day.
Acute Gout
[0075] Acute gout, or gout flares, can be treated according to the
following treatment schedule. This table indicates the original, or
intended, dosage amount, i.e., the dosage amount of colchicine
recommended absent concomitant administration of the drugs listed
below. This table also presents the dosage amount adjustment, or
the recommended colchicine dosage amount to be administered when
strong and moderate CYP3A4 and P-gp inhibitors are administered
concomitantly with colchicine when the patient is being treated for
a gout flare.
TABLE-US-00001 Colchicine Dose Recommendation Original Intended
Dose Drug (Total Dose) Dose Adjustment Strong CYP3A4 Regimen
Reduced by Two Thirds Inhibitors Clarithromycin 1.2 mg (2 tablets)
at the first 0.6 mg (1 tablet) .times. 1 dose. Erythromycin sign of
the flare followed Dose to be repeated no by 0.6 mg (1 tablet) one
hour earlier than 3 days. later. Dose to be repeated no earlier
than 3 days.
Chronic Gout
[0076] For chronic gout (prophylaxis of gout flares), an original
intended daily dosage amount is 1.2 mg or 6 mg. Alternatively, an
intended daily dosage amount of chronic gout can be as much as 2.4
mg per day. The daily dosage amount for chronic gout can be
administered at one time or dosed at intervals throughout the day,
e.g. twice daily, three times daily, or four times daily.
[0077] Chronic gout, with and without a concomitant dose of another
drug, can be treated according to the following treatment
schedule:
Colchicine Dose Adjustment for Co-Administration with Interacting
Drugs if No Alternative Available
TABLE-US-00002 [0078] Colchicine Dose Recommendation Drug Original
Intended Dose Dose Adjustment Clarithromycin 0.6 mg twice daily 0.3
mg once daily 0.6 mg once daily 0.3 mg once every other day
Erythromycin 0.6 mg twice daily 0.3 mg once daily 0.6 mg once daily
0.3 mg once every other day
[0079] The dosage amount of 0.3 mg once every other day is
administered either as 0.3 mg once every other day or 0.15 mg once
a day.
Familial Mediterranean Fever:
[0080] Familial Mediterranean Fever (FMF) can be treated according
to the following intended daily dosing schedule:
TABLE-US-00003 Daily dosage amount Age Usual Maximum Adults and
children > 12 years 1.2 mg 2.4 mg Children > 6 to 12 years
0.9 mg 1.8 mg Children 4 to 6 years 0.3 mg 1.8 mg
[0081] When colchicine is given to patients with FMF concomitantly
with other drugs, the adjusted (reduced) dosage amount of
colchicine, according to this embodiment, is provided in the table
below:
TABLE-US-00004 Concomitant Drug Noted or Anticipated Class or Food
Outcome Clinical Comment Strong CYP3A4 Significant increase in Use
colchicine with Inhibitors: colchicine plasma levels.sup.1; caution
at reduced clarithromycin fatal colchicine toxicity maximum dose of
0.3 mg has been reported with twice daily with increased
clarithromycin, a strong monitoring for adverse CYP3A4 inhibitor.
effects. In patients with Similarly, significant renal or hepatic
increase in colchicine impairment, use of plasma levels is
colchicine in conjunction anticipated with other with these drugs
is strong CYP3A4 contraindicated. inhibitors. Moderate CYP3A4
Significant increase in Use colchicine with inhibitors: colchicine
plasma caution at reduced erythromycin concentration is maximum
dose of 0.6 mg anticipated. twice daily with increased
Neuromuscular toxicity monitoring for adverse has been reported
with effects. In patients with diltiazem and verapamil renal or
hepatic interactions. impairment, use a maximum dose of 0.3 mg
twice daily.
[0082] Colchicine is one of the most widely used drugs for treating
familial Mediterranean fever (FMF). It has been reported that 5-10%
of FMF patients do not show a beneficial response to colchicine
administration. A polymorphism in the ABCB1 gene, the "ABCB1 3435 C
to T polymorphism" has been reported to correlate with this lack of
response to colchicine treatment, with patients with the homozygous
TT genotype exhibiting the most pronounced "non-responder"
phenotypes.
[0083] Accordingly, in another aspect, provided herein is a method
for treating a patient suffering from FMF, which patient is a
colchicine non-responder. In one embodiment, the patient is
homozygous for the TT genotype of the ABCB1 3435 C to T
polymorphism. The method entails the concomitant administration of
a Pgp inhibitor and colchicine to the patient. A preferred Pgp
inhibitor for use in this method is verapamil or cyclosporine-A,
more preferably a macrolide antibiotic, preferably dirithromycin,
erythromycin or roxithromycin, or, more preferably clarithromycin.
Dosage amounts of the Pgp inhibitor for this purpose correspond to
those called for in the prescribing information for the drug in
question. For clarithromycin, the dosage amounts are 500 to 1000 mg
per day and duration of clarithromycin dosing is preferably one,
two, or three days, repeated weekly or bi-weekly. Preferred
colchicine dosing regimens for this purpose are the same as used
for treatment of FMF in responders, though the doses of colchicine
administered may be increased as tolerated, e.g., up to two to
three times the typical doses.
[0084] These and other embodiments, advantages and features of the
present invention are further elaborated herein below.
DETAILED DESCRIPTION
[0085] Following multiple oral doses (0.6 mg twice daily), the mean
elimination half-life of colchicine in young healthy volunteers
(mean age 25 to 28 years of age) is 26.6 to 31.2 hours.
[0086] Pharmacy management systems are computer-based systems that
are widely used by commercial pharmacies to manage prescriptions
and to provide pharmacy and medical personnel with warnings and
guidance regarding drugs being administered to patients. Such
systems typically provide alerts warning either or both of health
care providers and patients when a drug that may be harmful to the
particular patient is prescribed. For example, such systems can
provide alerts warning that a patient has an allergy to a
prescribed drug, or is receiving concomitant administration of a
drug that can have a dangerous interaction with a prescribed drug.
U.S. Pat. Nos. 5,758,095, 5,833,599, 5,845,255, 6,014,631,
6,067,524, 6,112,182, 6,317,719, 6,356,873, and 7,072,840, each of
which is incorporated herein by reference, disclose various
pharmacy management systems and aspects thereof. Many pharmacy
management systems are now commercially available, e.g., CENTRICITY
Pharmacy from BDM Information Systems Ltd., General Electric
Healthcare, Waukesha, Wis., Rx30 Pharmacy Systems from Transaction
Data Systems, Inc., Ocoee, Fla., SPEED SCRIPT from Digital
Simplistics, Inc., Lenexa, Kans., and various pharmacy management
systems from OPUS-ISM, Hauppauge, N.Y.
[0087] In the specification and claims that follow, references will
be made to a number of terms which shall be defined to have the
following meaning.
[0088] The terms "a" and "an" do not denote a limitation of
quantity, but rather denote the presence of at least one of the
referenced item. The term "or" means "and/or". The terms
"comprising", "having", "including", and "containing" are to be
construed as open-ended terms (i.e., meaning "including, but not
limited to").
[0089] "Concomitant" and "concomitantly" as used herein refer to
the administration of at least two drugs to a patient either
simultaneously or within a time period during which the effects of
the first administered drug are still operative in the patient.
Thus, if the first drug is, e.g., clarithromycin and the second
drug is colchicine, the concomitant administration of the second
drug can occur as much as one to two weeks, preferably within one
to seven days, after the administration of the first drug. This is
because clarithromycin can exert a long-lasting inhibition of CYP3A
isozymes so that CYP3A activity in the patient may not return to
pre-clarithromycin-administration levels for as much as two weeks
after the cessation of clarithromycin administration. If colchicine
is the first drug, administration of a second drug would be
concomitant if done within 1 to 2 days, preferably 12 to 24
hours.
[0090] "Dosage amount" means an amount of a drug suitable to be
taken during a fixed period, usually during one day (i.e.,
daily).
[0091] "Dosage amount adapted for oral administration" means a
dosage amount that is of an amount deemed safe and effective for
the particular patient under the conditions specified. As used
herein and in the claims, this dosage amount is determined by
following the recommendations of the drug manufacturer's
Prescribing Information as approved by the US Food and Drug
Administration.
[0092] "Dosing regimen" means the dose of a drug taken at a first
time by a patient and the interval (time or symptomatic) and dosage
amounts at which any subsequent doses of the drug are taken by the
patient. Each dose may be of the same or a different dosage
amount.
[0093] A "dose" means the measured quantity of a drug to be taken
at one time by a patient.
[0094] A "patient" means a human or non-human animal in need of
medical treatment. Medical treatment can include treatment of an
existing condition, such as a disease or disorder, prophylactic or
preventative treatment, or diagnostic treatment. In preferred
embodiments the patient is human.
[0095] "Providing" means giving, administering, selling,
distributing, transferring (for profit or not), manufacturing,
compounding, or dispensing.
[0096] "Risk" means the probability or chance of adverse reaction,
injury, or other undesirable outcome arising from a medical
treatment. An "acceptable risk" means a measure of the risk of
harm, injury, or disease arising from a medical treatment that will
be tolerated by an individual or group. Whether a risk is
"acceptable" will depend upon the advantages that the individual or
group perceives to be obtainable in return for taking the risk,
whether they accept whatever scientific and other advice is offered
about the magnitude of the risk, and numerous other factors, both
political and social. An "acceptable risk" of an adverse reaction
means that an individual or a group in society is willing to take
or be subjected to the risk that the adverse reaction might occur
since the adverse reaction is one whose probability of occurrence
is small, or whose consequences are so slight, or the benefits
(perceived or real) of the active agent are so great. An
"unacceptable risk" of an adverse reaction means that an individual
or a group in society is unwilling to take or be subjected to the
risk that the adverse reaction might occur upon weighing the
probability of occurrence of the adverse reaction, the consequences
of the adverse reaction, and the benefits (perceived or real) of
the active agent. "At risk" means in a state or condition marked by
a high level of risk or susceptibility.
[0097] Pharmacokinetic parameters referred to herein describe the
in vivo characteristics of drug (or a metabolite or a surrogate
marker for the drug) over time. These include plasma concentration
(C), as well as C.sub.max, C.sub.n, C.sub.24, T.sub.max, and AUC.
"C.sub.max" is the measured plasma concentration of the active
agent at the point of maximum, or peak, concentration. "C.sub.min"
is the measured plasma concentration of the active agent at the
point of minimum concentration. "C.sub.n" is the measured plasma
concentration of the active agent at about n hours after
administration. "C.sub.24" is the measured plasma concentration of
the active agent at about 24 hours after administration. The term
"T.sub.max" refers to the time from drug administration until
C.sub.max is reached. "AUC" is the area under the curve of a graph
of the measured plasma concentration of an active agent vs. time,
measured from one time point to another time point. For example
AUC.sub.0-t is the area under the curve of plasma concentration
versus time from time 0 to time t, where time 0 is the time of
initial administration of the drug. Time t can be the last time
point with measurable plasma concentration for an individual
formulation. The AUC.sub.0-.infin. or AUC.sub.0-INF is the
calculated area under the curve of plasma concentration versus time
from time 0 to time infinity. In steady-state studies,
AUC.sub.0-.tau. is the area under the curve of plasma concentration
over the dosing interval (i.e., from time 0 to time .tau. (tau),
where tau is the length of the dosing interval. Other
pharmacokinetic parameters are the parameter K.sub.e or K.sub.el,
the terminal elimination rate constant calculated from a semi-log
plot of the plasma concentration versus time curve; t.sub.1/2 the
terminal elimination half-life, calculated as 0.693/K.sub.el. CL/F
denotes the apparent total body clearance after administration,
calculated as Total Dose/Total AUC.sub..infin.; and V.sub.area/F
denotes the apparent total volume of distribution after
administration, calculated as Total Dose/(Total
AUC.sub..infin..times.K.sub.el).
[0098] "Side effect" means a secondary effect resulting from taking
a drug. The secondary effect can be a negative (unfavorable) effect
(i.e., an adverse side effect) or a positive (favorable)
effect.
[0099] The most frequently reported adverse side effects to
colchicine therapy are gastrointestinal, specifically abdominal
pain with cramps, diarrhea, nausea, and vomiting. Less frequently
or rarely reported adverse side effects associated with colchicine
therapy include anorexia, agranulocytosis, allergic dermatitis,
allergic reactions, alopecia, angioedema, aplastic anemia, bone
marrow depression, myopathy, neuropathy, skin rash,
thrombocytopenic disorder, and urticaria.
[0100] Whether a patient experiences an adverse side effect can be
determined by obtaining information from the patient regarding
onset of certain symptoms which may be indicative of the adverse
side effect, results of diagnostic tests indicative of the adverse
side effect, and the like.
[0101] The following examples further illustrate aspects of this
disclosure but should not be construed as in any way limiting its
scope. In particular, the conditions are merely exemplary and can
be readily varied by one of ordinary skill in the art.
EXAMPLES
Example 1
Pharmacokinetic Study in Healthy Adults of Single Vs. Multiple Oral
Doses of Colchicine Tablets
[0102] This study was a single-center, open-label, single-sequence,
two-period study to evaluate the pharmacokinetic profile of
colchicine following single and multiple oral doses of colchicine
tablets, 0.6 mg, in healthy volunteers.
[0103] In Period 1, study subjects received a 0.6-mg dose of
colchicine after an overnight fast of at least 10 hours. In Period
2, subjects received a 0.6-mg dose of colchicine in the morning and
the evening (approximately 12 hours later) for 10 days (steady
state regimen). Subjects received a light breakfast served 60
minutes following dose administration in the morning and the
evening dose was administered 90 minutes after an evening meal on
Days 15 through 24 only. On Day 25, the colchicine dose was
administered after an overnight fast of at least 10 hours and lunch
was served 4 hours post-dose. Study periods were separated by a
14-day washout. Following the single dose and the last dose of the
multiple dose regimen (beginning on the mornings of Day 1 and Day
25, respectively), blood samples were collected (6 mL each) from
each subject within 1 hour prior to dosing and after dose
administration at study hours 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12,
and 24 (while confined) and 36, 48, 72, and 96 (on an outpatient
basis). Plasma concentrations of colchicine and its metabolites
were determined using validated LC/MS-MS methods.
[0104] Thirteen healthy, non-smoking subjects with a mean age of
25.5 years (range 19 to 38 years) and within 15% of ideal body
weight were enrolled in this study. All subjects completed both
dosing periods according to protocol.
[0105] After a single dose, plasma concentrations are no longer
quantifiable 24 hours post-dose in all but 1 subject. After the
last dose of the steady state regimen, concentrations remained
quantifiable for 48 to 72 hours. Review of individual subject data
shows that no subject experienced a secondary colchicine peak,
either following a single dose or upon multiple dosing.
[0106] All 2-O-demethylcolchicine (2-DMC) concentrations were below
the level of quantitation (LOQ, 0.2 ng/mL) and only one sample from
1 subject (of 13 subjects) had a detectable 3-O-demethylcolchicine
(3-DMC) concentration, which was near the level of quantitation.
Therefore, metabolites are not discussed further.
[0107] In healthy adults, colchicine appears to be readily absorbed
when given orally, reaching a mean maximum plasma concentration of
2.5 ng/mL in 1.5 hours after a single dose. The drug is distributed
widely, with an apparent volume of distribution of 540 L, greatly
exceeding total body water. The elimination half-life as calculated
following a single oral dose is approximately 5 hours. Levels were
not detectable by 24 hours post-dose and this is therefore not an
accurate estimate. Pharmacokinetic parameter values are summarized
in the table below.
[0108] Review of trough plasma concentrations indicates that steady
state was attained by approximately the eighth day of dosing for
most subjects. Colchicine may have a diurnal variation reflected in
the observed Cmin concentrations at steady state. Cmin
concentrations prior to the morning dose are approximately 12%
higher than the Cmin concentrations prior to the evening dose (Day
23 and Day 24). The mean Cmin concentration observed on Day 25 was
0.907 ng/mL.
[0109] Colchicine accumulated following administration of multiple
doses to an extent greater than expected. Exposure was nearly
two-fold higher (approximately 1.7 based on AUC [Day 25
AUC.sub.0-.tau./Day 1 AUC.sub.0-.infin.] and approximately 1.5
based on Cmax [Day 25 C.sub.max/Day 1 C.sub.max]). This observation
could be attributable to an underestimation of AUC.infin. following
a single dose. With the higher plasma levels that occur with
repeated dosing, a longer terminal elimination half life is
apparent, 26.6 hours. Pharmacokinetic parameter values are
summarized in the tables below.
TABLE-US-00005 TABLE 1 Colchicine Pharmacokinetic Parameter Values
Following Administration of A Single Oral Dose of Colchicine 0.6 mg
in Healthy Adults (N = 13) AUC.sub.0-t AUC.sub.0-inf C.sub.max
T.sub.max K.sub.el T.sub.1/2 (pg-hr/mL) (pg-hr/mL) (pg/mL) (hr)
(1/hr) (hr) MEAN 10508.54 12281.90 2470.77 1.50 0.1829 4.95 STDEV
3544.82 4423.34 706.98 0.54 0.0592 4.43 % CV 33.73 36.02 28.61
36.00 32.39 89.54 MEDIAN 10560.90 11451.45 2714.00 1.50 0.1992 3.48
MIN 4812.88 7252.66 1584.00 1.00 0.0359 2.84 MAX 18128.65 23838.48
3977.00 3.00 0.2443 19.29
TABLE-US-00006 TABLE 2 Colchicine Pharmacokinetic Parameter Values
Following Administration of Multiple (b.i.d.) Oral Doses of
Colchicine 0.6 mg in Healthy Adults (N = 13) AUC.sub.0-t
AUC.sub.0-.tau. AUC.sub.0-inf C.sub.max C.sub.min C.sub.ave
T.sub.max K.sub.el T.sub.1/2 (pg-hr/mL) (pg-hr/mL) (pg-hr/mL)
(pg/mL) (pg/mL) (pg/mL) (hr) (1/hr) (hr) MEAN 43576.96 29056.23
54198.77 3553.15 906.51 1210.68 1.31 0.03 26.60 STDEV 9333.26
4531.30 9214.54 843.45 152.19 188.80 0.60 0.00 4.33 % CV 21.42
15.59 17.00 23.74 16.79 15.59 45.61 16.34 16.26 MEDIAN 41925.10
28452.15 54113.43 3734.00 903.50 1185.51 1.00 0.03 26.51 MIN
29328.78 20791.98 37599.76 1977.00 636.23 866.33 0.50 0.02 20.82
MAX 58265.35 36083.95 67944.65 4957.00 1149.67 1503.50 3.00 0.03
33.65
TABLE-US-00007 TABLE 3 Mean (% CV) Colchicine Pharmacokinetic
Parameter Values Following Administration of Single and Multiple
(b.i.d.) Oral Doses of Colchicine 0.6 mg in Healthy Adults Vd/F (L)
CL/F (L/hr) Colchicine 0.6-mg Single Dose (N = 13) Day 1 540.5
341.5 (31.0) (54.4) Colchicine 0.6 mg b.i.d. .times. 10 days Day 25
1150 30.3 (18.73) (19.0) CL = Dose/AUC.sub.0-t (Calculated from
mean values) Vd = CL/Ke (Calculated from mean values)
[0110] In the above table, the parameter CL/F denotes the apparent
total body clearance after administration, calculated as Total
Dose/Total AUC0-.sub.tau; and V.sub.d/F denotes the apparent total
volume of distribution after administration, calculated as Total
Dose/(Total AUC.sub..infin..times.K.sub.el).
Example 2
Clinical Drug-Drug Interaction Study of Colchicine and
Clarithromycin
[0111] A single-center, open-label, one sequence, two-period study
was carried out in 23 healthy subjects. On Day 1, a single 0.6-mg
dose of colchicine was administered. After completing a 21-day
washout period, all subjects received 250 mg of clarithromycin
administered twice daily for 7 days (Days 22 through 29), a
sufficient dose and duration to inhibit CYP3A4 and Pgp. On the
final day (Day 29), a single dose of colchicine was co-administered
with the clarithromycin dose.
[0112] When combined with steady-state clarithromycin, there is a
significant increase in exposure to colchicine as compared to when
colchicine is given alone: the mean C.sub.max and AUC.sub.0-t
concentrations increased 167% and 250%, respectively. In addition,
co-administration of clarithromycin and colchicine resulted in an
increase of 233% in the plasma elimination half-life (t1/2) of
colchicine and a 75% decrease in apparent clearance (CL/F). A
summary of the mean (% CV) colchicine pharmacokinetic parameters
for Day 1 (colchicine administered alone) and Day 29 (colchicine
co-administered with steady-state clarithromycin) are given in the
table below and illustrated in the table that follows.
TABLE-US-00008 TABLE 4 Comparison of Single-Dose Colchicine (0.6
mg, Alone) and Single-Dose Colchicine (0.6 mg) Co-Administered with
Steady-State Clarithromycin in Healthy Adults C.sub.max
T.sub.max.sup.1 AUC.sub.0-t AUC.sub..infin. Ke Vd/F CL/F t.sub.1/2
DAY (ng/mL) (h) (ng h/mL) (ng h/mL) (h.sup.-1) (L) (L/hr) (h)
Colchicine Alone (n = 23) 1 3 1.00 12 16 0.132 432 46.8 9 (30.97)
(0.5-2.0) (37.6) (49.6) (46.87) (56.1) (43.7) (126.4) Colchicine +
Clarithromycin (n = 23) 29 8 1.0 42 53 0.0298 493 12 30 (23.74)
(1.0-5.0) (23.3) (22.8) (90.82) (33.69) (23.8) (41.37) p value
<0.0001 0.05061 <0.0001 <0.0001 <0.0001 <0.0001
<0.0001 0.0001 .sup.1T.sub.max mean (range)
[0113] Recitation of ranges of values herein are merely intended to
serve as a shorthand method of referring individually to each
separate value falling within the range, unless otherwise indicated
herein, and each separate value is incorporated into the
specification as if it were individually recited herein. The
endpoints of all ranges directed to the same component or property
are inclusive and independently combinable.
[0114] All methods described herein can be performed in a suitable
order unless otherwise indicated or clearly contradicted by
context. The use of any and all examples, or exemplary language
(e.g., "such as") herein is intended to better illuminate the
disclosure and is non-limiting unless otherwise specified. No
language in the specification should be construed as indicating
that any non-claimed element as essential to the practice of the
claimed embodiments. Unless defined otherwise, technical and
scientific terms used herein have the same meaning as is commonly
understood by one of skill in the art to which this disclosure
belongs. The terms wt %, weight percent, percent by weight, etc.
are equivalent and interchangeable
[0115] Embodiments are described herein, including the best modes
known to the inventors. Variations of such embodiments will become
apparent to those of ordinary skill in the art upon reading the
foregoing description. The skilled artisan is expected to employ
such variations as appropriate, and the disclosed methods are
expected to be practiced otherwise than as specifically described
herein. Accordingly, all modifications and equivalents of the
subject matter recited in the claims appended hereto are included
to the extent permitted by applicable law. Moreover, any
combination of the above-described elements in all possible
variations thereof is encompassed unless otherwise indicated herein
or otherwise clearly contradicted by context.
* * * * *