U.S. patent application number 13/302017 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 | 20120065992 13/302017 |
Document ID | / |
Family ID | 42319513 |
Filed Date | 2012-03-15 |
United States Patent
Application |
20120065992 |
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: |
42319513 |
Appl. No.: |
13/302017 |
Filed: |
November 22, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12909171 |
Oct 21, 2010 |
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13302017 |
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12372046 |
Feb 17, 2009 |
7820681 |
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12909171 |
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61138141 |
Jan 14, 2009 |
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61152067 |
Feb 12, 2009 |
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Current U.S.
Class: |
705/2 |
Current CPC
Class: |
A61P 19/06 20180101;
G16H 20/10 20180101; A61K 31/165 20130101; A61K 31/496 20130101;
G16H 70/40 20180101; A61P 19/02 20180101; A61P 29/00 20180101; A61K
31/165 20130101; A61K 2300/00 20130101; A61K 31/496 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
705/2 |
International
Class: |
G06Q 50/22 20120101
G06Q050/22 |
Claims
1. A method for using a first drug, comprising: a pharmacy
receiving a prescription for the first drug for a patient who is
concomitantly being treated with a second drug, and the pharmacy
dispensing the first drug in response to receipt of the
prescription, wherein the dispensing is preceded by: entering, into
a computer program, a unique patient identifier for said patient
and a first drug identifier for the first drug linked to the
patient identifier so as to indicate that the first drug is to be
administered to the patient, wherein responsive to the entering the
computer program performs a method comprising: issuing a drug-drug
interaction alert when a) the first drug identifier for the first
drug is entered linked to the 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 the 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 method 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 U.S. application Ser. No.
12/909,171, filed Oct. 21, 2010, which is a continuation of U.S.
application Ser. No. 12/372,046, filed Feb. 17, 2009, now U.S. Pat.
No. 7,820,681, issued Oct. 26, 2010, which claims priority from
U.S. Provisional Application Ser. Nos. 61/138,141 filed Dec. 17,
2008 and 61/152,067 filed Feb. 12, 2009, all of which are hereby
incorporated by reference in their entirety.
FIELD OF THE DISCLOSURE
[0002] This disclosure relates to methods allowing for the
co-administration of colchicine together with one or more second
active agents for therapeutic purposes with improved safety
compared to prior methods of administration.
BACKGROUND
[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 an alkaloid found in extracts of
Colchicum autumnale, Gloriosa superba, and other plants. It 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, resulting in effects in cells with high turnover rates
such as those in the gastrointestinal tract and bone marrow. The
primary adverse side effects of colchicine therapy include
gastrointestinal upset such as diarrhea and nausea.
[0004] Colchicine has a narrow therapeutic index. The margin
between an effective dose and a toxic dose of colchicine is much
narrower than that of many 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.
[0005] 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.
[0006] Gout (or gouty arthritis) is a disease caused by a build up
of uric acid in the joints. 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 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. 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 manner, gout
progresses from acute gout to chronic gout, which involves repeated
episodes of joint pain.
[0007] 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.
[0008] Cytochrome p450 (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 and different CYP isozymes
may preferentially metabolize different drugs. 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 second active agents. 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. 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.
[0009] P-glycoprotein (P-gp) is an ATP-dependent cell surface
transporter molecule that acts as an ATPase efflux pump for
multiple cytotoxic agents, including colchicine. P-gp actively
pumps certain compounds, including drugs such as colchicine, out of
cells. P-gp 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).
[0010] Since colchicine acts intracellularly, the combined effects
of CYP3A4 inhibition and P-gp inhibition by second active agents
that also interact with CYP3A4 and P-gp can cause colchicine
toxicity in patients taking what would be a safe dose of colchicine
in the absence of concomitant second agent administration. 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.
[0011] There accordingly remains a need for improved methods for
administering colchicine to individuals who are concomitantly being
treated with second active agents so as to reduce the possibility
of colchicine toxicity while maintaining the sometimes life-saving
advantages of being able to administer the two (or more) agents
concomitantly. The present disclosure addresses this need and
provides further advantages.
SUMMARY
[0012] In one embodiment, a method of treating an individual in
need of treatment with colchicine comprises concomitantly
administering to the individual colchicine and another drug, for
example, ketoconazole or ritonavir or cyclosporine, wherein the
colchicine is administered as a dosing regimen with a 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 at least one additional colchicine dose within
about 12 hours and no more frequently than once every hour wherein
each additional colchicine dose is no greater than about 0.6 mg.
According to another embodiment, the other drug is, for example,
verapamil or diltiazem, and the starting colchicine dose during
coadministration with the other drug is no more than about 1.2 mg
colchicine, 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.
[0013] In another aspect, a method of using colchicine comprises
increasing the blood plasma levels of colchicine in a individual
being administered doses of about 0.6 mg or less of colchicine to
treat a colchicine-treatable condition, said method comprising the
concomitant dosing of the individual with a sufficient amount of
ketoconazole to increase the C.sub.max of colchicine by about 90%,
or to increase the AUC.sub.0-t of colchicine in the individual by
about 190%, or to increase the AUC.sub.0-inf of colchicine in the
individual by about 205%, or to decrease the clearance of
colchicine by about 70%, compared to the C.sub.max, AUC.sub.0-t,
AUC.sub.0-inf, or clearance in a matched individual not
administered concomitant ketoconazole.
[0014] In yet another aspect, a method of using colchicine
comprises increasing the blood plasma levels of colchicine in an
individual being administered doses of about 0.6 mg or less of
colchicine to treat a colchicine-treatable condition, said method
comprising the concomitant dosing of the individual with a
sufficient amount of ritonavir to increase the C.sub.max of
colchicine by about 170%, or to increase the AUC.sub.0-t of
colchicine in the individual by about 245%, or to decrease the
clearance of colchicine by about 70%, compared to the C.sub.max
AUC.sub.0-t, or clearance in a matched individual not administered
concomitant ritonavir.
[0015] In another embodiment, a method for using colchicine
comprises a pharmacy receiving a prescription for colchicine for a
patient who is concomitantly being treated with ketoconazole or
ritonavir or verapamil, and the pharmacy dispensing colchicine in
response to receipt of the prescription, wherein the dispensing is
preceded by: entering, 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,
wherein the computer has been 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 ketoconazole or ritonavir or verapamil is being
concomitantly administered to the patient, wherein, 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 that
ketoconazole or ritonavir 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 about 0.6 mg colchicine, 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 wherein each
additional colchicine dose is no greater than about 0.6 mg.
[0016] A method of treating a patient with colchicine comprises
administering an adjusted daily dosage amount of colchicine to the
patient who is receiving concomitant administration of ritonavir,
wherein the adjusted daily dosage amount of colchicine is about 25%
to 50% of an intended daily dosage amount of colchicine, and
wherein the intended daily dosage amount of colchicine is a dose
suitable for the patient if the patient were not receiving
concomitant ritonavir.
[0017] A method of treating a patient with colchicine comprises
administering an adjusted daily dosage amount of colchicine to the
patient who is receiving concomitant administration of
ketoconazole, wherein the adjusted daily dosage amount of
colchicine is about 25% to 50% of an intended daily dosage amount
of colchicine, and wherein the intended daily dosage amount of
colchicine is a daily dosage amount suitable for the patient if the
patient were not receiving concomitant ketoconazole.
[0018] A method of treating an individual in need of treatment for
gout flares, comprises concomitantly administering colchicine and
azithromycin, and carefully monitoring the individual for potential
toxicity. The method further comprises adjusting the dose of
colchicine or azithromycin as necessary to avoid adverse side
effects.
[0019] A method of treating an individual with colchicine comprises
concomitantly administering colchicine and verapamil, and carefully
monitoring the individual for signs and symptoms of adverse side
effects. The method further comprises administering an adjusted
daily dosage amount of colchicine to the patient who is receiving
concomitant administration of verapamil, wherein the adjusted daily
dosage amount of colchicine is about 50% to 75% of an intended
daily dosage amount of colchicine, and wherein the intended daily
dosage amount of colchicine is a daily dosage amount suitable for a
patient if the patient were not receiving concomitant
verapamil.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] 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.
[0021] 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, =colchicine alone, .diamond-solid.=colchicine plus
clarithromycin. See Example 2.
[0022] FIG. 3 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 and
steady-state cyclosporine in healthy adults. Y axis=colchicine
concentration, ng/mL, X axis=time in hours, N=18,
.tangle-solidup.=colchicine alone, =colchicine plus clarithromycin,
.box-solid.=colchicine plus cyclosporine.
[0023] FIG. 4 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 ketoconazole and
steady-state ritonavir in healthy adults. Y axis=colchicine
concentration, ng/mL, X axis=time in hours, N=18,
.tangle-solidup.=colchicine alone, =colchicine plus ketoconazole,
.box-solid.=colchicine plus ritonavir.
[0024] FIG. 5 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 azithromycin and
steady-state diltiazem in healthy adults. Y axis=colchicine
concentration, ng/mL, X axis=time in hours, N=18,
.tangle-solidup.=colchicine alone, =colchicine plus azithromycin,
.box-solid.=colchicine plus diltiazem.
[0025] These and other embodiments, advantages and features of the
present invention become clear when detailed description is
provided in subsequent sections.
DETAILED DESCRIPTION
[0026] Disclosed herein are methods for safely administering
colchicine concomitantly with a second active agent, wherein the
second active agent is a CYP3A4 inhibitor, a P-gp inhibitor, or
both. Exemplary second active agents that are CYP3A4 and P-gp
inhibitors are azithromycin, ketoconazole, ritonavir, diltiazem,
verapamil and cyclosporine. It has now been discovered that certain
reduced or limited colchicine dosage amounts, when administered
with concomitantly administered recommended dosage amounts of
second active agents that are CYP3A4 inhibitors, P-gp inhibitors,
or both, 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 dosages in
the absence of concomitant administration with the second active
agent. Thus, colchicine and second active agents that are CYP3A4
inhibitors, P-gp inhibitors, or both, can be administered
concomitantly with improved safety when colchicine is administered
as disclosed herein.
[0027] Without being held to theory, it has been hypothesized by
the inventors herein that P-gp inhibition is more important in the
elimination of colchicine than CYP3A4 inhibition. The CYP3A4 and
P-gp inhibition potential of clarithromycin, azithromycin,
ketoconazole, ritonavir, diltiazem and cyclosporine are given in
Table 1. Based on their level of P-gp inhibition, it was predicted
that clarithromycin and cyclosporine will increase colchicine
concentrations more than ketoconazole or ritonavir, which will
increase colchicine levels more than verapamil, azithromycin or
diltiazem. The results presented herein confirm this
hypothesis.
TABLE-US-00001 TABLE 1 CYP3A4 and P-gp inhibition potential of
second active agents Drug CYP3A Inhibition potential P-gp
Inhibition potential Clarithromycin +++++ +++++ Cyclosporine +++++
+++++ Ketoconazole +++++ +++ Ritonavir +++++ +++ Verapamil ++ ++
Diltiazem + + Azithromycin + +
[0028] Ritonavir (Norvir.RTM., Abbott Laboratories) is an inhibitor
of Human Immunodeficiency Virus (HIV) protease and is approved for
the treatment of HIV-infection when used as part of a highly active
antiretroviral therapy (HAART) regimen at the recommended dose of
600 mg twice daily. Although a very potent and effective protease
inhibitor at the recommended dose, ritonavir is not well tolerated
by HIV-infected patients at the approved dose and therefore, is
generally not used clinically as a sole, therapeutic protease
inhibitor within a HAART regimen. Rather, ritonavir is used more
often as a pharmacokinetic enhancer or `boosting agent` when
combined with other approved protease inhibitors that are CYP3A4
and P-gp substrates and also have inherent bioavailability issues,
such as poor bioavailability due to first pass effect Improving the
pharmacokinetic disposition of other protease inhibitors is
possible due to the potent CYP3A4 and P-gp inhibitory activity
ritonavir possesses. Sub-therapeutic ritonavir doses are used to
achieve pharmacokinetic enhancement of the co-administered protease
inhibitors; typically 100 mg of ritonavir administered twice daily
is the ritonavir dose used in combination with the primary protease
inhibitor. This low-dose ritonavir regimen boosts the
bioavailability of the second protease inhibitor without
contributing significantly to the adverse event profile of the
HAART regimen.
[0029] Cyclosporine (Neoral.RTM., Novartis Pharmaceuticals
Corporation) is the active principle in Neoral.RTM. an oral
formulation that immediately forms a microemulsion in an aqueous
environment. Cyclosporine is indicated for kidney, liver, and heart
transplantation; rheumatoid arthritis and psoriasis. Cyclosporine
is extensively metabolized by the CYP3A4 enzyme system in the
liver, and to a lesser degree in the gastrointestinal tract, and
the kidney. The metabolism of cyclosporine can be altered by the
co-administration of a variety of agents.
[0030] Ketoconazole is a synthetic broad-spectrum antifungal agent
available in scored white tablets, each containing 200 mg
ketoconazole base for oral administration. Ketoconazole tablets are
indicated for the treatment of the following systemic fungal
infections: candidiasis, chronic mucocutaneous candidiasis, oral
thrush, candiduria, blastomycosis, coccidioidomycosis,
histoplasmosis, chromomycosis, and paracoccidioidomycosis.
Ketoconazole is a potent inhibitor of the CYP3A4 enzyme system.
Co-administration of ketoconazole and drugs primarily metabolized
by the CYP3A4 enzyme may result in increased plasma concentrations
of the drugs that could increase or prolong both therapeutic and
adverse side effects.
[0031] Azithromycin is a macrolide antibiotic indicated for the
treatment of patients with mild to moderate infections caused by
susceptible strains of the designated microorganisms in specific
conditions. Azithromycin remains the sole agent developed and
marketed within the azalide macrolide subclass. Due to its dibasic
structure, azithromycin has demonstrated unique pharmacokinetic
properties that differ significantly from those of classic
macrolide agents. Azithromycin's pharmacokinetics are characterized
by low concentrations in serum, secondary to rapid and significant
uptake by fibroblasts and acute reactant cells such as
polymorphonuclear leukocytes (PMNs), monocytes, and lymphocytes.
Azithromycin is a weak to moderate CYP3A4 inhibitor.
[0032] Diltiazem (Cardizem.RTM. CD, Biovail Pharmaceuticals, Inc.
[Biovail]) is an extended-release (ER) calcium ion influx inhibitor
available in blue capsules, each containing 240 mg diltiazem
hydrochloride for oral administration. Diltiazem ER capsules are
indicated for the treatment of hypertension and the management of
chronic stable angina and angina due to coronary artery spasm.
Diltiazem is a CYP3A4 and P-gp inhibitor.
[0033] Verapamil HCl ER (Mylan Pharmaceuticals, Inc.) is a calcium
ion influx inhibitor available in a pale green, capsule shaped,
film-coated tablets, each containing 240 mg verapamil hydrochloride
for oral administration. Verapamil HCl ER tablets are indicated for
the management of hypertension. Verapamil HCl ER is a potent CYP3A4
and P-gp inhibitor.
[0034] In one embodiment, colchicine is administered to an
individual suffering from a condition treatable with colchicine,
and the concomitant second active agent (e.g., ketoconazole,
ritonavir, cyclosporine, verapamil, or diltiazem or any other
CYP3A4 or P-gp inhibitor) is administered concurrently while the
colchicine administration is reduced, or the individual has
recently completed a dosing regimen of the second active agent, in
which case the colchicine administration may still be reduced for a
period of time.
[0035] In one embodiment, disclosed herein is a method of
administering colchicine and a second active agent (e.g.,
ketoconazole, ritonavir, or cyclosporine) wherein an individual 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
specifically no greater than about 0.3 mg and the individual is an
adult individual or a pediatric individual. Specifically, the
starting colchicine dose is about 0.6 mg or about 0.3 mg, and each
additional colchicine dose is about 0.3 mg. In one embodiment, when
additional doses are administered, only two, three, or four
additional colchicine doses are administered within about 24 hours.
Specifically, the individual is an adult individual 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.
[0036] In one embodiment, disclosed herein is a method of
administering colchicine and a second active agent (e.g., verapamil
or diltiazem) wherein an individual is administered the colchicine
according to a colchicine dosing regimen of a single starting
colchicine dose of no more than about 1.2 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 specifically no greater than about 0.3 mg or 0.6
mg and the individual is an adult individual or a pediatric
individual. Specifically, the starting colchicine dose is about 0.6
mg or 1.2 mg, and each additional colchicine dose is about 0.3 mg
or 0.6 mg. In one embodiment, when additional doses are
administered, only two, three, or four additional colchicine doses
are administered within about 24 hours. Specifically, the
individual is an adult individual and the starting colchicine dose
is about 1.2 mg, and each additional colchicine dose, if any, is
about 0.3 mg or 0.6 mg. In one embodiment, only three additional
colchicine doses are administered within about 24 hours.
[0037] In one embodiment, the second active agent is ketoconazole
or ritonavir. In one embodiment, the ketoconazole is administered
to the individual at a dosage of about 200 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. In another embodiment, the ritonavir is administered to the
individual at a dosage of about 200 to 1200 mg daily (e.g., in
2.times.100 mg doses or 2.times.600 mg doses) 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.
In an exemplary 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. More preferably, 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.
[0038] In one embodiment, the second active agent (e.g.,
ketoconazole or ritonavir or cyclosporine) is administered to the
individual before the colchicine is administered to the individual,
and wherein the administration of second active agent is terminated
no more than about fourteen days prior to the initiation of
colchicine administration. For example, the method comprises
administering colchicine to an individual also taking a second
active agent (e.g., ketoconazole or ritonavir or cyclosporine), or
having completed treatment with the second active agent within the
prior 14 days, the individual being administered a single dose 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.
According to this embodiment if the second active agent is instead
verapamil or diltiazem, if the second active agent is terminated no
more than about fourteen days prior to the initiation of the
colchicine administration to treat a gout flare, the single dose of
colchicine is about 1.2 mg not to be repeated within a 3-day
period.
[0039] In another aspect, herein disclosed is a method for
increasing the blood plasma levels of colchicine in an individual
to whom colchicine is being administered to treat or prevent a
colchicine-responsive condition. This method comprises the
concomitant dosing of the individual with a sufficient amount of
ketoconazole to increase the C.sub.max of colchicine by about 90%,
or to increase the AUC.sub.0-t of colchicine in the individual by
about 190%, or to increase the AUC.sub.0-inf of colchicine in the
individual by about 205%, or to decrease the clearance of
colchicine by about 70%, compared to the C.sub.max, AUC.sub.0-t, or
clearance in the same or a matched individual when not being
administered a concomitant ketoconazole. In a specific embodiment,
the individual is being administered no more than hourly doses of
about 0.6 mg of colchicine or less, and the amount of ketoconazole
is about 200 mg. In one embodiment, the single dose is one 0.6 mg
colchicine tablet.
[0040] In yet another aspect, herein disclosed is a method for
increasing the blood plasma levels of colchicine in an individual
to whom colchicine is being administered to treat or prevent a
colchicine-responsive condition. This method comprises the
concomitant dosing of the individual with a sufficient amount of
ritonavir to increase the C.sub.max of colchicine by about 170%, or
to increase the AUC.sub.0-t of colchicine in the individual by
about 245%, or to decrease the clearance of colchicine by about
70%, compared to the C.sub.max, AUC.sub.0-t, or clearance in the
same or a matched individual when not being administered
concomitant ritonavir. In a specific embodiment, the individual is
being administered no more than hourly doses of about 0.6 mg of
colchicine or less, and the amount of ritonavir is about 200 to
about 1200 mg. In one embodiment, the single dose is one 0.6 mg
colchicine tablet.
[0041] In one embodiment, a method of treating a patient with
colchicine comprises administering an adjusted daily dosage amount
of colchicine to the patient who is receiving concomitant
administration of ritonavir, wherein the adjusted daily dosage
amount of colchicine is 25% to 50% of an intended daily dosage
amount of colchicine, and wherein the intended daily dosage amount
of colchicine is a daily dosage amount suitable for the patient if
the patient were not receiving concomitant ritonavir. Treating is,
for example, to prevent gout flares, to treat acute gout, or to
treat familial Mediterranean fever. When the colchicine is
administered to prevent gout flares, the adjusted daily dosage
amount of colchicine may reduced from a 0.6 mg twice daily intended
dose to a 0.6 mg once daily adjusted dose. Alternatively, when the
colchicine is administered to prevent gout flares, wherein the
adjusted daily dosage amount of colchicine is reduced from a 0.6 mg
once daily intended dose to a 0.3 mg once daily adjusted dose. In
one embodiment, when treating is for acute gout, the intended daily
dosage amount is 1.8 to 2.4 mg, and the maximum adjusted daily
dosage amount is 0.6 mg, not to be repeated within 3 days. In
another embodiment, treating is for acute gout, the intended daily
dosage amount is 2.4 to 4.8 mg and the maximum adjusted daily
dosage amount is 0.6 to 1.2 mg, not to be repeated within 3 days.
In yet another embodiment, treating is for familial Mediterranean
fever and the daily dosage amount 1.2 to 2.4 mg for adults, and the
maximum adjusted daily dosage amount is 0.6 mg, given, for example,
in two 0.3 mg doses. In another embodiment, treating is for
familial Mediterranean fever and the intended daily dosage amount
is 0.9 to 1.8 mg for children 6-12 years or 4-6 years, and the
maximum adjusted daily dosage amount is 0.6 mg, given, for example,
in two 0.3 mg doses. The concomitantly administered dose of
ritonavir is, for example, 200 mg per day. In one embodiment, the
ritonavir is administered to the patient before the colchicine is
administered to the patient, and wherein the administration of
ritonavir is terminated no more than about fourteen days prior to
the initiation of colchicine administration. The method optionally
further comprises carefully monitoring the individual for potential
toxicity. Any 0.3 mg dose contemplated in this method can be a
single 0.3 mg dosage form or one-half a 0.6 mg dosage form, e.g.
one-half a 0.6 mg colchicine tablet.
[0042] A method of treating a patient with colchicine comprises
administering an adjusted daily dosage amount of colchicine to the
patient who is receiving concomitant administration of
ketoconazole, wherein the adjusted daily dosage amount of
colchicine is 25% to 50% of an intended daily dosage amount of
colchicine, and wherein the intended daily dosage amount of
colchicine is a daily dosage amount suitable for the patient if the
patient were not receiving concomitant ketoconazole. Treating is,
for example, to prevent gout flares, to treat acute gout, or to
treat familial Mediterranean fever. When the colchicine is
administered to prevent gout flares, the adjusted daily dosage
amount of colchicine may reduced from a 0.6 mg twice daily intended
dose to a 0.6 mg once daily adjusted dose. Alternatively, when the
colchicine is administered to prevent gout flares, wherein the
adjusted daily dosage amount of colchicine is reduced from a 0.6 mg
once daily intended dose to a 0.3 mg once daily adjusted dose. In
one embodiment, when treating is for acute gout, the intended daily
dosage amount is 1.8 to 2.4 mg, and the maximum adjusted daily
dosage amount is 0.6 mg, not to be repeated within 3 days. In
another embodiment, treating is for acute gout, the intended daily
dosage amount is 2.4 to 4.8 mg and the maximum adjusted daily
dosage amount is 0.6 to 1.2 mg, not to be repeated within 3 days.
In yet another embodiment, treating is for familial Mediterranean
fever and the daily dosage amount 1.2 to 2.4 mg for adults, and the
maximum adjusted daily dosage amount is 0.6 mg, given, for example,
in two 0.3 mg doses. In another embodiment, treating is for
familial Mediterranean fever and the intended daily dosage amount
is 0.9 to 1.8 mg for children 6-12 years or 4-6 years, and the
maximum adjusted daily dosage amount is 0.6 mg, given, for example,
in two 0.3 mg doses. The concomitantly administered dose of
ketoconazole is, for example, 250 mg per day. In one embodiment,
the ketoconazole is administered to the patient before the
colchicine is administered to the patient, and wherein the
administration of ketoconazole is terminated no more than about
fourteen days prior to the initiation of colchicine administration.
The method optionally further comprises carefully monitoring the
individual for potential toxicity. Any 0.3 mg dose contemplated in
this method can be a single 0.3 mg dosage form or one-half a 0.6 mg
dosage form, e.g. one-half a 0.6 mg colchicine tablet.
[0043] A method of treating a patient with colchicine comprises
administering an adjusted daily dosage amount of colchicine to the
patient who is receiving concomitant administration of
cyclosporine, wherein the adjusted daily dosage amount of
colchicine is 25% to 50% of an intended daily dosage amount of
colchicine, and wherein the intended daily dosage amount of
colchicine is a daily dosage amount suitable for the patient if the
patient were not receiving concomitant cyclosporine. Treating is,
for example, to prevent gout flares, to treat acute gout, or to
treat familial Mediterranean fever. When the colchicine is
administered to prevent gout flares, the adjusted daily dosage
amount of colchicine may reduced from a 0.6 mg twice daily intended
dose to a 0.3 mg once daily adjusted dose. Alternatively, when the
colchicine is administered to prevent gout flares, wherein the
adjusted daily dosage amount of colchicine is reduced from a 0.6 mg
once daily intended dose to a 0.3 mg once every other day adjusted
dose. In one embodiment, when treating is for acute gout, the
intended daily dosage amount is 1.8 to 2.4 mg, and the maximum
adjusted daily dosage amount is 0.6 mg, not to be repeated within 3
days. In another embodiment, treating is for acute gout, the
intended daily dosage amount is 2.4 to 4.8 mg and the maximum
adjusted daily dosage amount is 0.6 to 1.2 mg, not to be repeated
within 3 days. In yet another embodiment, treating is for familial
Mediterranean fever and the daily dosage amount 1.2 to 2.4 mg for
adults, and the maximum adjusted daily dosage amount is 0.6 mg,
given, for example, in two 0.3 mg doses. In another embodiment,
treating is for familial Mediterranean fever and the intended daily
dosage amount is 0.9 to 1.8 mg for children 6-12 years or 4-6
years, and the maximum adjusted daily dosage amount is 0.6 mg,
given, for example, in two 0.3 mg doses. The concomitantly
administered dose of cyclosporine can be various dosage strengths
administered per day, and can be administered as an oral
preparation, topically, or intravenously. In one embodiment, the
cyclosporine is administered to the patient before the colchicine
is administered to the patient, and wherein the administration of
cyclosporine is terminated no more than about fourteen days prior
to the initiation of colchicine administration. The method
optionally further comprises carefully monitoring the individual
for potential toxicity. Any 0.3 mg dose contemplated in this method
can be a single 0.3 mg dosage form or one-half a 0.6 mg dosage
form, e.g. one-half a 0.6 mg colchicine tablet.
[0044] In another embodiment, colchicine is concomitantly
administered with azithromycin. Concomitant administration of
azithromycin with colchicine increases exposure to colchicine
approximately 46% and thus has the potential to produce colchicine
toxicity. During concomitant use of azithromycin and colchicine,
the physician should carefully monitor individuals for any signs or
symptoms of colchicine toxicity. Additionally, dosing adjustments
to either the colchicine and/or the azithromycin may be necessary
to avoid adverse side effects.
[0045] A method of treating a patient with colchicine comprises
administering an adjusted daily dosage amount of colchicine to the
patient who is receiving concomitant administration of verapamil,
wherein the adjusted daily dosage amount of colchicine is 50% to
75% of an intended daily dosage amount of colchicine, and wherein
the intended daily dosage amount of colchicine is a daily dosage
amount suitable for the patient if the patient were not receiving
concomitant verapamil. Treating is, for example, to prevent gout
flares, to treat acute gout, or to treat familial Mediterranean
fever. When the colchicine is administered to prevent gout flares,
the adjusted daily dosage amount of colchicine may reduced from a
0.6 mg twice daily intended dose to a 0.3 mg once daily adjusted
dose. In one embodiment, when treating is for acute gout, the
intended daily dosage amount is 1.8 to 2.4 mg, and the maximum
adjusted daily dosage amount is 1.2 mg. In another embodiment,
treating is for acute gout, the intended daily dosage amount is 2.4
to 4.8 mg and the maximum adjusted daily dosage amount is about
one-third the intended daily dosage amount. In yet another
embodiment, treating is for familial Mediterranean fever and the
daily dosage amount 1.2 to 2.4 mg for adults, and the maximum
adjusted daily dosage amount is 1.2 mg, given, for example, in two
0.6 mg doses. In one embodiment, the verapamil is administered to
the patient before the colchicine is administered to the patient,
and wherein the administration of verapamil is terminated no more
than about fourteen days prior to the initiation of colchicine
administration. The method optionally further comprises carefully
monitoring the individual for potential toxicity. Any 0.3 mg dose
contemplated in this method can be a single 0.3 mg dosage form or
one-half a 0.6 mg dosage form, e.g. one-half a 0.6 mg colchicine
tablet.
[0046] Disclosed herein are specific dosage reductions of
colchicine that improve safety when colchicine is co-administered
with certain active agents. The dose of colchicine recommended for
administration without co-administration of certain other active
agents, such as CYP3A4 or P-gp inhibitors, is referred to as an
intended daily dosage amount. The reduced or modified daily dosage
amount determined from the experiments presented herein is referred
to as an adjusted daily dosage amount. An adjusted daily dosage
amount is thus a daily dosage amount that can be safely
co-administered with a second active agent as disclosed herein. A
dose adjustment is thus a dose of colchicine and does not include
cessation of colchicine, that is, a dose of 0 mg of colchicine.
[0047] 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 BehOet's disease. In some
embodiments, the treatment with colchicine is either palliative or
prophylactic. The gout may be acute gout, e.g. a gout flare, or
chronic gout.
Acute Gout:
[0048] Acute gout, or gout flares, can be treated according to the
following treatment schedule. This table indicates the original, or
intended, dose, i.e., the dose of colchicine recommended absent
concomitant administration of the drugs listed below. This table
also presents the dose adjustment of the present invention, or the
recommended colchicine dose to be administered when the strong and
moderate CYP3A4 and P-gp inhibitors are administered concomitantly
with colchicine when the patient is being treated for acute gout,
or an acute gout flare.
TABLE-US-00002 Colchicine Dose Recommendation Drug Original
Intended Dose (Total Dose) Dose Adjustment Strong CYP3A4 Inhibitors
Regimen Reduced by Two Thirds Erythromycin 1.2 mg (2 tablets) at
the first sign 0.6 mg (1 tablet) .times. 1 dose. Ketoconazole of
the flare followed by 0.6 mg (1 Dose to be repeated no earlier
Ritonavir tablet) one hour later. Dose to be than 3 days. repeated
no earlier than 3 days. Moderate CYP3A4 Inhibitors Regimen Reduced
by One Third Diltiazem 1.2 mg (2 tablets) at the first sign 1.2 mg
(2 tablets) .times. 1 dose. Verapamil of the flare followed by 0.6
mg (1 Dose to be repeated no earlier tablet) one hour later. Dose
to be than 3 days. repeated no earlier than 3 days. Strong P-gp
Inhibitors Regimen Reduced by Two Thirds Cyclosporine 1.2 mg (2
tablets) at the first sign 0.6 mg (1 tablet) .times. 1 dose. of the
flare followed by 0.6 mg (1 Dose to be repeated no earlier tablet)
one hour later. Dose to be than 3 days. repeated no earlier than 3
days.
Chronic Gout:
[0049] For chronic gout, 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.
[0050] 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-00003 [0051] 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
Cyclosporine 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 Ritonavir
0.6 mg twice daily 0.6 mg once daily 0.6 mg once daily 0.3 mg once
daily
Familial Mediterranean Fever:
[0052] Familial Mediterranean Fever (FMF) can be treated according
to the following intended daily dosing schedule:
TABLE-US-00004 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
[0053] 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-00005 Concomitant Drug Class or Noted or Anticipated Food
Outcome Clinical Comment Strong CYP3A4 Inhibitors: Significant
increase in Use colchicine with caution atazanavir, clarithromycin,
colchicine plasma levels.sup.1; at reduced maximum dose of
indinavir, itraconazole, fatal colchicine toxicity has 0.3 mg twice
daily with ketoconazole, nefazodone, been reported with increased
monitoring for nelfinavir, ritonavir, clarithromycin, a strong
adverse effects. In patients saquinavir, telithromycin CYP3A4
inhibitor. with renal or hepatic Similarly, significant impairment,
use of colchicine increase in colchicine plasma in conjunction with
these levels is anticipated with drugs is contraindicated. other
strong CYP3A4 inhibitors. Moderate CYP3A4 Significant increase in
Use colchicine with caution inhibitors: amprenavir, colchicine
plasma at reduced maximum dose of aprepitant, diltiazem,
concentration is anticipated. 0.6 mg twice daily with erythromycin,
fluconazole, Neuromuscular toxicity has increased monitoring for
fosamprenavir, grapefruit been reported with diltiazem adverse
effects. In patients juice, verapamil and verapamil interactions.
with renal or hepatic impairment, use a maximum dose of 0.3 mg
twice daily. Strong P-gp Inhibitors Significant increase in Use
colchicine with caution e.g. Cyclosporine, colchicine plasma
levels.sup.1; at reduced maximum dose of ranolazine. fatal
colchicine toxicity has 0.3 mg twice daily with been reported with
increased monitoring for cyclosporine, a strong P-gp adverse
effects. In patients inhibitor. Similarly, with renal or hepatic
significant increase in impairment, use of colchicine colchicine
plasma levels is in conjunction with these anticipated with other
strong drugs is contraindicated. P-gp inhibitors.
[0054] 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 individuals. 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.
[0055] In another aspect, herein disclosed are methods for using
colchicine which methods involve the use of pharmacy management
systems.
[0056] 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 second active agent
(e.g., ketoconazole or ritonavir) 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 second active agent (e.g.,
ketoconazole or ritonavir) that is an inhibitor of CYP3A4 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 second active agent (e.g., ketoconazole or ritonavir) 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.
[0057] The drug-drug interaction alert is preferably 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.
[0058] In one aspect, the identifier indicating that ketoconazole
is being concomitantly administered to the patient is an identifier
indicating that the second active agent is ketoconazole and is
linked to at least one further identifier indicating that the
ketoconazole is prescribed so that 200 mg of ketoconazole 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 ketoconazole
is being concomitantly administered to the patient is an identifier
indicating that the second active agent is ketoconazole 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 ketoconazole is prescribed so that about 200 mg
of ketoconazole is to be ingested by the patient daily, in which
case the colchicine dosing regimen is 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. In one
embodiment, the dosing regimen calls for the about 0.3 mg
colchicine dose every six to eight hours. In another embodiment,
the dosing regimen calls for one dose of the colchicine every eight
to twelve hours.
[0059] In yet another preferred aspect, the identifier indicating
that ketoconazole is being concomitantly administered to the
patient is an identifier indicating that the second active agent is
ketoconazole 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 ketoconazole is
prescribed so that about 200 mg of ketoconazole 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.
[0060] A preferred 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.
[0061] In another aspect, the identifier indicating that ritonavir
is being concomitantly administered to the patient is an identifier
indicating that the second active agent is ritonavir and is linked
to at least one further identifier indicating that the ritonavir is
prescribed so that 200 or 1200 mg of ritonavir 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 ritonavir is
being concomitantly administered to the patient is an identifier
indicating that the second active agent is ritonavir 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 ritonavir is prescribed so that about 1200 mg
of ritonavir is to be ingested by the patient daily, in which case
the colchicine dosing regimen is 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. In one
embodiment, the dosing regimen calls for the about 0.3 mg
colchicine dose every six to eight hours. In another embodiment,
the dosing regimen calls for one dose of the colchicine every eight
to twelve hours.
[0062] In yet another aspect, the identifier indicating that
ritonavir is being concomitantly administered to the patient is an
identifier indicating that the second active agent is ritonavir 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 ritonavir is prescribed so that about 1200 mg
of ritonavir 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.
[0063] Also disclosed herein is a dosage adjustment method for
administering colchicine to a patient to treat a medical condition,
the patient concomitantly treated with a second active agent. The
second active agent may be, for example, ritonavir, ketoconazole,
cyclosporine, verapamil, or diltiazem. The method comprises
determining a first colchicine dosing regimen (the colchicine
dosing regimen suitable for administration in the absence of
co-administration with a second active agent, which dosing regimen
may consist of one or more doses of colchicine); and determining a
second active agent dosing regimen; and administering the second
active agent to the patient at the second active agent dosing
regimen while concomitantly administering colchicine to the patient
according to a second colchicine dosing regimen, which may consist
of one or more reduced colchicine doses. The second colchicine
dosing regimen is a fraction of the first colchicine dosing
regimen, where the fraction is obtained by administering reduced
colchicine doses or by reducing the frequency of colchicine doses,
and wherein the fraction is less than or equal to about 2/3 or less
than or equal to about 1/2 or less than or equal to about 1/3.
[0064] According to this embodiment, upon the administering the
second active agent to the patient at the second active agent
dosing regimen while concomitantly administering colchicine to the
patient at the second colchicine dosing regimen, 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. In one
embodiment, if the second colchicine dosing regimen comprises a
"first" colchicine dose, and one or more "subsequent" colchicine
doses, each subsequent colchicine dose may be the same as the first
dose, or a fraction of the first dose. 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 one example,
the second colchicine dosing regimen is once-a-day, twice-a-day,
three-times-a-day or four-times-a-day. In a variation of this
example, the initial treatment day in, a second colchicine dosing
regimen that lasts for more than one day, has one more dose
administered than are administered each subsequent day.
[0065] Preferably the second active agent is selected from
ketoconazole, cyclosporine, ritonavir, verapamil, or diltiazem. The
specific conditions are selected from gout, FMF, thrombocytopenic
purpura, and BehOet's disease. In one 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, or
prevention, of flares. In another embodiment, the fraction of
colchicine administered to the patient concomitantly with a second
active agent that is a CYP3A4 or P-gp inhibitor is 1/3 or 1/2 the
original intended amount of colchicine and treatment with
colchicine is initiated subsequent to or at the same time as
initiation of treatment with the second active agent.
[0066] 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.
[0067] Accordingly, in another aspect, provided herein is a method
for treating a patient suffering from FMF, which patient is a
colchicine non-responder. Preferably, the patient is homozygous for
the TT genotype of the ABCB1 3435 C to T polymorphism. The method
entails the concomitant administration of a P-gp inhibitor and
colchicine to the patient. Exemplary P-gp inhibitors include
ketoconazole and ritonavir. Preferred dosages of the P-gp inhibitor
for this purpose correspond to those called for in the prescribing
information for the drug in question. For ketoconazole, an
exemplary dosage is 200 mg per day. For ritonavir, an exemplary
dosage is 200 or 1200 mg per day. Specific 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.
[0068] 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
[0069] 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.
[0070] 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.
[0071] 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.
[0072] 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.
[0073] 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-demethylcolchciine
(3-DMC) concentration, which was near the level of quantitation.
Therefore, metabolites are not discussed further.
[0074] 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.
[0075] 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.
[0076] 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 Tables 3-5.
TABLE-US-00006 TABLE 3 Colchicine Pharmacokinetic Parameter Values
Following Administration of A Single Oral Dose of Colchicine 0.6 mg
in Healthy Adults (N = 13) MEAN STDEV % CV MEDIAN MIN MAX
AUC.sub.0-t 10494.66 3544.08 33.77 10560.90 4812.88 18091.85
(pg-hr/mL) AUC.sub.0-inf 12268.18 4422.08 36.05 11451.45 7252.66
23801.68 (pg-hr/mL) Cmax 2450.15 702.11 28.66 2480.00 1584.00
3977.00 (pg/mL) Tmax 1.50 0.54 36.00 1.50 1.00 3.00 (hr) K.sub.el
0.1829 0.0592 32.38 0.1992 0.0359 0.2443 (1/hr) T.sub.1/2 4.95 4.43
89.54 3.48 2.84 19.29 (hr)
TABLE-US-00007 TABLE 4 Colchicine Pharmacokinetic Parameter Values
Following Administration of Multiple (b.i.d.) Oral Doses of
Colchicine 0.6 mg in Healthy Adults (N = 13) MEAN STDEV % CV MEDIAN
MIN MAX AUC.sub.0-t 43576.96 9333.26 21.42 41925.10 29328.78
58265.35 (pg-hr/mL) AUC.sub.0-.tau. 20366.61 3322.12 16.31 20423.08
13719.18 25495.25 (pg-hr/mL) AUC.sub.0-inf 54198.77 9214.54 17.00
54113.43 37599.76 67944.65 (pg-hr/mL) C.sub.max 3553.15 843.45
23.74 3734.00 1977.00 4957.00 (pg/mL) C.sub.min 906.51 152.19 16.79
903.50 636.23 1149.67 (pg/mL) C.sub.ave 1697.22 276.84 16.31
1701.92 1143.26 2124.60 (pg/mL) T.sub.max 1.31 0.60 45.61 1.00 0.50
3.00 (hr) K.sub.el 0.0267 0.0044 16.34 0.0261 0.0206 0.0333 (1/hr)
T.sub.1/2 26.60 4.33 16.26 26.51 20.82 33.65 (hr)
TABLE-US-00008 TABLE 5 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 1 341 54.1
(54.4) (31.0) 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)
[0077] In tables, 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). FIG. 1 shows mean colchicine
plasma concentrations following administration of single and
multiple oral doses of colchicine 0.6 mg in healthy adults.
Example 2
Clinical Drug-Drug Interaction Study of Colchicine and
Clarithromycin
[0078] 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.
[0079] 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 Table 5.
TABLE-US-00009 TABLE 6 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 Arithmetic Mean (%
CV) Colchicine + Colchicine Clarithromycin Parameter (units) (N =
23) (N = 23) AUC.sub.0-t (ng hr/mL) 12.37 (37.64) 41.95 (23.31)
AUC.sub.0-inf (ng hr/mL) 15.53 (49.6) 52.62 (22.84) C.sub.max
(ng/mL) 2.84 (30.97) 8.44 (17.63) T.sub.max (hr)* 1.50 (0.50-2.00)
1.00 (0.50-2.00) CL/F (L/hr) 46.8 (43.68) 12.0 (23.75)
[0080] 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. Based on the foregoing data, it is concluded that
the dose of colchicine co-administered with clarithromycin should
be reduced by 2/3.
Example 3
Clinical Drug-Drug Interaction Study of Colchicine and
Cyclosporine
[0081] This study was an open-label, non-randomized, single-center,
one-sequence, two-period drug interaction study conducted in
healthy male and female volunteers. Twenty-four (24) non-smoking,
non-obese adult volunteers were enrolled. All subjects were dosed
and studied as a single cohort, with each subject receiving the
same treatment in a non-randomized fashion.
[0082] A single dose of colchicine, 0.6 mg, was administered alone
on Day 1, and then co-administered with cyclosporine on Day 15.
Cyclosporine was administered as a single-dose (1.times.100 mg
capsule) on the morning of Day 15. A 14 day washout period was
completed after the first colchicine dose on Day 1 and prior to the
co-administration of colchicine and cyclosporine doses on Day
15.
[0083] Serial blood samples were collected by individual
venipuncture up to 96 hours following drug administration on Day 1
and Day 15. Blood samples for determination of colchicine plasma
concentrations were obtained at time zero (pre-dose) and after dose
administration at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours
post-dose on a confined basis. Subjects were then return to the
clinic on a non-confined basis for continued blood sampling
collection at 36, 48, 72, and 96 hours post-dose administration on
Days 2-5 (Period 1) and Days 16-19 (Period 2). Cyclosporine plasma
concentrations were not measured.
TABLE-US-00010 TABLE 7 Comparison of Single-Dose Colchicine (0.6
mg, Alone) and Single-Dose Colchicine (0.6 mg) Co-Administered with
Steady-State Cyclosporine in Healthy Adults Arithmetic Mean (% CV)
Colchicine + Colchicine Cyclosporine Parameter (units) (N = 23) (N
= 23) AUC.sub.0-t (ng hr/mL) 12.55 39.83 AUC.sub.0-inf (ng hr/mL)
15.00 47.31 C.sub.max (ng/mL) 2.72 8.82 T.sub.max (hr)* 1.15 1.13
CL/F (L/hr) 48.24 13.42
[0084] FIG. 3 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 and
steady-state cyclosporine in healthy adults. Based on the foregoing
data, the dose of colchicine co-administered with cyclosporine
should be reduced by approximately 1/2 to 3/4.
Example 4
Clinical Drug-Drug Interaction Study of Colchicine and
Ritonavir
[0085] An open-label, non-randomized, single-center, one-sequence,
two-period drug interaction study was conducted in healthy male and
female volunteers; there will be a 14-day washout between the two
periods. Twenty-four (24) non-smoking, non-obese adult volunteers
were enrolled. All subjects were dosed and studied as a single
cohort, with each subject receiving the same treatment in a
non-randomized fashion.
[0086] All subjects received a single 0.6-mg dose of colchicine on
Day 1 administered under standard fasting conditions, followed by a
14-day washout period completed on an outpatient basis. At
discharge on Day 2, study subjects were instructed to return to the
clinical site on the mornings and evenings of Days 15 through 18 to
receive two daily dosage amounts of ritonavir (1.times.100 mg
ritonavir capsule twice daily (every 12 hours) on Days 15-18) in a
`directly-observed` fashion; after taking the first dose of
ritonavir, subjects remained in the clinic for observation for 1
hour post-dose administration on Day 15. On the evening of Day 18,
study participants remained at the clinic for their final study
confinement period. In the morning on Day 19, study subjects
received a single 0.6 mg colchicine dose with a single 100 mg
ritonavir dose and study subjects received the final 100 mg
ritonavir dose 12 hours later in the evening on Day 19 under
standard fasting conditions.
[0087] Serial blood samples were collected by individual
venipuncture up to 96 hours following drug administration on Day 1
and Day 19. Blood samples for determination of colchicine plasma
concentrations were obtained at time zero (pre-dose) and after dose
administration at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours
post-dose on an inpatient basis. Subjects returned to the clinic on
an outpatient basis for continued blood sampling collection at 36,
48, 72, and 96 hours post-dose administration. Ritonavir plasma
concentrations were not measured.
TABLE-US-00011 TABLE 8 Comparison of Single-Dose Colchicine (0.6
mg, Alone) and Single-Dose Colchicine (0.6 mg) Co-Administered with
Steady-State Ritonovir in Healthy Adults: ln-transformed data
Colchicine + Colchicine Alone Ritonovir % Ratio C.sub.max (pg/mL),
geometric 1798.37 4835.39 268.88 mean AUC.sub.0-t (pg h/mL),
7642.71 27793.08 363.65 geometric mean AUC.sub..infin. (pg h/mL),
9551.74 33771.36 353.56 geometric mean
TABLE-US-00012 TABLE 9 Comparison of Single-Dose Colchicine (0.6
mg, Alone) and Single-Dose Colchicine (0.6 mg) Co-Administered with
Steady-State Ritonavir in Healthy Adults Arithmetic Mean (% CV)
Median (Range) for T.sub.max Colchicine + Ritonavir Colchicine
Alone Parameter (units) (N = 18) (N = 18) AUC.sub.0-t (ng hr/mL)
29.05 (30.76) 8.41 (47.46) AUC.sub.0-.infin. (ng hr/mL) 35.28
(29.79) 10.41 (45.48) C.sub.max (ng/mL) 4.99 (25.18) 1.87 (28.19)
T.sub.max (hr) 1.5 (1-1.5) 1 (0.5-1.5) CL/F (L/hr) 18.59 (31.58)
67.93 (39.47)
[0088] Following exposure to 100 mg b.i.d..times.5 days, there was
a significant increase in exposure to a single 0.6-mg colchicine
(approximately 245%). Mean peak colchicine concentration increased
by approximately 170%. Total apparent oral clearance was decreased
by 70% with co-administration. T.sub.max is not affected.
Elimination half-life could not be estimated accurately as plasma
concentrations were not quantifiable after 24 hours.
[0089] FIG. 4 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 ritonavir and
steady-state ketoconazole in healthy adults. Based on the foregoing
data, the dose of colchicine co-administered with ritonavir should
be reduced by approximately 1/2.
Example 5
Clinical Drug-Drug Interaction Study of Colchicine and
Ketoconazole
[0090] This study was an open-label, non-randomized, single-center,
one-sequence, two-period drug interaction study conducted in
healthy male and female volunteers; there will be a 14-day washout
between the two periods. Twenty-four (24) non-smoking, non-obese
adult volunteers were enrolled.
[0091] A single dose of colchicine, 0.6 mg, was administered alone
on Day 1, and then co-administered with ketoconazole on Day 19 (AM
dose). Ketoconazole was administered for 5 consecutive days [200 mg
twice daily (every 12 hours)] beginning on the morning of Day 15,
with the last 200 mg ketoconazole dose administered on the evening
on Day 19. Total study participation, exclusive of up to 28 days of
screening, was approximately 24 days, during which subjects will be
confined on two occasions for a total confinement of approximately
3 days.
[0092] Serial blood samples were collected by individual
venipuncture up to 96 hours following drug administration on Day 1
and Day 19. Blood samples for determination of colchicine plasma
concentrations were obtained at time zero (pre-dose) and after dose
administration at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours
post-dose on an inpatient basis. Subjects then returnee to the
clinic on an outpatient basis for continued blood sampling
collection at 36, 48, 72, and 96 hours post-dose administration.
Ketoconazole plasma concentrations were not measured.
TABLE-US-00013 TABLE 10 Comparison of Single-Dose Colchicine (0.6
mg, Alone) and Single-Dose Colchicine (0.6 mg) Co-Administered with
Steady-State Ketoconazole in Healthy Adults: ln-transformed data
Colchicine + Colchicine Alone Ketoconazole % Ratio C.sub.max
(pg/mL), geometric 2598.28 5078.50 195.46 mean AUC.sub.0-t (pg
h/mL), 11087.99 33223.80 299.64 geometric mean AUC.sub..infin. (pg
h/mL), 13185.92 42143.00 319.61 geometric mean
TABLE-US-00014 TABLE 11 Comparison of Single-Dose Colchicine (0.6
mg, Alone) and Single-Dose Colchicine (0.6 mg) Co-Administered with
Steady-State Ketoconazole in Healthy Adults Arithmetic Mean (% CV)
Colchicine + Colchicine Ketoconazole Parameter (units) (N = 23) (N
= 23) AUC.sub.0-t (pg hr/mL) 11988.61 34382.82 AUC.sub.0-inf (pg
hr/mL) 14314.09 43688.90 C.sub.max (pg/mL) 2779.08 5266.92
T.sub.max (hr)* 1.00 1.02 CL/F (L/hr) 49301.09 14797.94 *Median
(Range) for T.sub.max
[0093] Following administration of ketoconazole 200 mg
b.i.d..times.5 days, there was a significant increase in exposure
to a single oral dose of colchicine 0.6 mg (C.sub.max and
AUC.sub.0-t increased by 90% and 190%, respectively, and
AUC.sub.0-.infin. increased by about 205%). Total apparent oral
clearance decreased by 70% with co-administration. Elimination
half-life could not be estimated accurately as plasma
concentrations were not quantifiable after 24 hours.
[0094] FIG. 4 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 ritonavir and
steady-state ketoconazole in healthy adults. Based on the foregoing
data, the dose of colchicine co-administered with ketoconazole
should be reduced by approximately 1/2.
Example 6
Clinical Drug-Drug Interaction Study of Colchicine and
Azithromycin
[0095] This study was an open-label, non-randomized, single-center,
one-sequence, two-period drug interaction study conducted in
healthy male and female volunteers; there was a 14-day washout
between the two periods. Twenty-four (24) non-smoking, non-obese
adult volunteers were enrolled. All subjects were dosed and studied
as a single cohort, with each subject receiving the same treatment
in a non-randomized fashion.
[0096] A single dose of colchicine, 0.6 mg, was administered alone
on Day 1, and then co-administered with the azithromycin on Day 19.
Azithromycin was administered for 5 consecutive days (2.times.250
mg once daily [Day 15 only] and then 1.times.250 mg once daily Days
16-19) beginning on the morning of Day 15, with the last 250 mg
azithromycin dose administered on the morning on Day 19. Total
study participation, exclusive of up to 28 days of screening, was
approximately 24 days, during which subjects were confined on two
occasions for a total confinement of approximately 3 days.
[0097] Serial blood samples were collected by individual
venipuncture up to 96 hours following drug administration on Day 1
and Day 19. Blood samples for determination of colchicine plasma
concentrations were obtained at time zero (pre-dose) and after dose
administration at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours
post-dose on an inpatient basis. Subjects returned to the clinic on
an outpatient basis for continued blood sampling collection at 36,
48, 72, and 96 hours post-dose administration. Azithromycin plasma
concentrations were not measured.
TABLE-US-00015 TABLE 12 Comparison of Single-Dose Colchicine (0.6
mg, Alone) and Single-Dose Colchicine (0.6 mg) Co-Administered with
Steady-State Azithromycin in Healthy Adults Colchicine + Colchicine
Alone Azithromycin % Ratio C.sub.max (pg/mL), geometric 2535.94
2856.22 112.63 mean AUC.sub.0-t (pg h/mL), 10971.51 16090.52 146.66
geometric mean AUC.sub..infin. (pg h/mL), 12931.80 18312.83 141.61
geometric mean
TABLE-US-00016 TABLE 13 Comparison of Single-Dose Colchicine (0.6
mg, Alone) and Single-Dose Colchicine (0.6 mg) Co-Administered with
Steady-State Azithromycin in Healthy Adults Arithmetic Mean (% CV)
Median (Range) for T.sub.max Colchicine + Azithromycin Colchicine
Alone Parameter (units) (N = 21) (N = 21) AUC.sub.0-t (ng hr/mL)
17.16 (37.78) 11.98 (45.81) AUC.sub.0-.infin. (ng hr/mL) 19.61
(39.15) 14.13 (46.73) C.sub.max (ng/mL) 3.05 (39.54) 2.74 (41.52)
T.sub.max (hr) 1.5 (0.5-3) 1.0 (0.5-3) t.sub.1/2 (hr) 6.71
(68.34).sup.1 6.07 (66.15).sup.1 CL/F (L/hr) 35.01 (37.26) 50.24
(40.31)
[0098] Following administration of azithromycin 500 mg on Day 1
followed by 250 mg.times.4 days, exposure to colchicine is
increased (approximately 46% for AUC.sub.0-t and approximately 40%
for AUC.sub.0-.infin.). Mean peak colchicine concentration
increased by approximately 12% and total apparent oral clearance
decreased approximately 30% with co-administration. T.sub.max was
not affected.
[0099] FIG. 5 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 azithromycin and
steady-state diltiazem in healthy adults.
Example 7
Clinical Drug-Drug Interaction study of Colchicine and
Diltiazem
[0100] This study was an open-label, non-randomized, single-center,
one-sequence, two-period drug interaction study conducted in
healthy male and female volunteers. Twenty-four (24) non-smoking,
non-obese adult volunteers were enrolled. All subjects were dosed
and studied as a single cohort, with each subject receiving the
same treatment in a non-randomized fashion.
[0101] As single dose of colchicine, 0.6 mg, was administered alone
on Day 1, and then co-administered with diltiazem ER on Day 21.
Diltiazem ER was administered for 7 consecutive days (1.times.240
mg capsule once daily on Days 15-21) beginning on the morning of
Day 15, with the last 240 mg diltiazem ER dose administered on the
morning on Day 21. A 14-day washout period was completed after the
first colchicine dose on Day 1 and prior to the administration of
the first diltiazem ER dose on Day 15.
[0102] Serial blood samples were collected by individual
venipuncture up to 96 hours following drug administration on Day 1
and Day 21. Blood samples for determination of colchicine plasma
concentrations were obtained at time zero (pre-dose) and after dose
administration at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours
post-dose on an inpatient basis. Subjects returned to the clinic on
an outpatient basis for continued blood sampling collection at 36,
48, 72, and 96 hours post-dose administration. Diltiazem plasma
concentrations were not measured.
TABLE-US-00017 TABLE 14 Comparison of Single-Dose Colchicine (0.6
mg, Alone) and Single-Dose Colchicine (0.6 mg) Co-Administered with
Steady-State Diltiazem in Healthy Adults Colchicine + Colchicine
Alone Diltiazem % Ratio C.sub.max (pg/mL), geometric 2006.42
2583.22 128.75 mean AUC.sub.0-t (pg h/mL), 9154.55 15740.37 171.94
geometric mean AUC.sub..infin. (pg h/mL), 11022.30 19902.98 180.57
geometric mean
TABLE-US-00018 TABLE 15 Comparison of Single-Dose Colchicine (0.6
mg, Alone) and Single-Dose Colchicine (0.6 mg) Co-Administered with
Steady-State Diltiazem in Healthy Adults Arithmetic Mean (% CV)
Median (Range) for T.sub.max Colchicine + Diltiazem Colchicine
Alone Parameter (units) (N = 20) (N = 20) AUC.sub.0-t (ng hr/mL)
17.73 10.04 AUC.sub.0-.infin. (ng hr/mL) 22.49 12.03 C.sub.max
(ng/mL) 2.80 2.17 T.sub.max (hr) 1.48 1.15 t.sub.1/2 (hr) 12.50
5.51 CL/F (L/hr) 463.49 395.83
[0103] FIG. 5 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 azithromycin and
steady-state diltiazem in healthy adults.
Example 8
Clinical Drug-Drug Interaction Study of Colchicine and
Verapamil
[0104] This study was an open-label, non-randomized, single-center,
one-sequence, two-period drug interaction study conducted in
healthy male and female volunteers. Twenty-four (24) non-smoking,
non-obese adult volunteers were enrolled. All subjects were dosed
and studied as a single cohort, with each subject receiving the
same treatment in a non-randomized fashion.
[0105] A single dose of colchicine, 0.6 mg, was administered alone
on Day 1, and then co-administered with verapamil HCl ER on Day 19.
Verapamil HCl ER was administered for 5 consecutive days
(1.times.240 mg tablet once daily on Days 15-19) beginning on the
morning of Day 15, with the last 240 mg verapamil HCl ER dose
administered on the morning on Day 19. A 14-day washout period was
completed after the first colchicine dose on Day 1 and prior to the
administration of the first verapamil HCL ER dose on Day 15.
[0106] Serial blood samples were collected by individual
venipuncture up to 96 hours following drug administration on Day 1
and Day 19. Blood samples for determination of colchicine plasma
concentrations were obtained at time zero (pre-dose) and after dose
administration at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours
post-dose on a confined basis. Subjects returned to the clinic on a
non-confined basis for continued blood sampling collection at 36,
48, 72, and 96 hours post-dose administration on Days 2-5 (Period
1) and Days 20-23 (Period 2). Verapamil plasma concentrations were
not measured.
TABLE-US-00019 TABLE 16 Comparison of Single-Dose Colchicine (0.6
mg, Alone) and Single-Dose Colchicine (0.6 mg) Co-Administered with
Steady-State Verapamil in Healthy Adults Colchicine + Colchicine
Alone Verapamil % Ratio C.sub.max (pg/mL), geometric 2768.77
3639.68 131.45 mean AUC.sub.0-t (pg h/mL), 12256.40 23889.21 194.94
geometric mean AUC.sub..infin. (pg h/mL), 14415.79 29556.75 205.03
geometric mean
TABLE-US-00020 TABLE 17 Comparison of Single-Dose Colchicine (0.6
mg, Alone) and Single-Dose Colchicine (0.6 mg) Co-Administered with
Steady-State Verapamil in Healthy Adults Arithmetic Mean (% CV)
Median (Range) for T.sub.max Colchicine + Verapamil Colchicine
Alone Parameter (units) (N = 24) (N = 24) AUC.sub.0-t (ng hr/mL)
24.64 13.09 AUC.sub.0-.infin. (ng hr/mL) 30.59 15.37 C.sub.max
(ng/mL) 3.85 2.97 T.sub.max (hr) 1.15 1.22 t.sub.1/2 (hr) 17.17
6.24 CL/F (L/hr) 21.01 43.93
[0107] 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.
[0108] 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.
[0109] 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.
[0110] 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").
[0111] "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.
[0112] A "dose" means the measured quantity of a drug to be taken
at one time by a patient.
[0113] A "dosage amount" means an amount of a drug suitable to be
taken during a fixed period, usually during one day (i.e. daily). A
"daily dosage amount" is the total dosage amount taken in one day,
that is, a 24 hour period.
[0114] "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 different.
[0115] 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.
[0116] "Providing" means giving, administering, selling,
distributing, transferring (for profit or not), manufacturing,
compounding, or dispensing.
[0117] "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.
[0118] 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., AUC.sub..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).
[0119] "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.
[0120] 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.
[0121] 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.
[0122] 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.
* * * * *