Clinical trial NCT00983242: Drug-Drug Interaction Between Colchicine and Verapamil ER
Official title: A One-Directional, Open Label Drug Interaction Study to Investigate the Effects of Multiple Dose Verapamil HCl ER on Single Dose Pharmacokinetics of Colchicine in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pharmacokinetics
Lead sponsor: Mutual Pharmaceutical Company, Inc.
Sponsor class: INDUSTRY
First posted: 2009-09-24
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: Colchicine is a substrate for both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Verapamil hydrochloride is a potent inhibitor of cytochrome P450 (CYP) 3A4 and P-gp. This study will evaluate the effect of multiple doses of extended-release verapamil hydrochloride (verapamil HCl ER) on the pharmacokinetic profile of a single 0.6 mg dose of colchicine. A secondary objective is to evaluate the safety and tolerability of this regimen in healthy volunteers. All study subjects will be monitored for adverse events throughout the study period.

Detailed description: Colchicine is a substrate for both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Verapamil hydrochloride is a potent inhibitor of cytochrome P450 (CYP) 3A4 and P-gp. This study will evaluate the effect of multiple doses of extended-release verapamil hydrochloride (verapamil HCl ER) on the pharmacokinetic profile of a single 0.6 mg dose of colchicine. On study Day 1 after a fast of at least 10 hours, twenty-four healthy, non-smoking, non-obese, non-pregnant adult volunteers between the ages of 18 and 45 will be given one dose of colchicine (1 x 0.6 mg tablet). Fasting will continue for 4 hours after the dose. Blood samples will be drawn from all participants before dosing and for 24 hours post-dose on a confined basis at times sufficient to adequately define the pharmacokinetics of colchicine. Blood sampling will then continue on a non-confined basis on Days 2-5. After a 14 day washout period, on Day 15 subjects will return to the clinic for dosing of verapamil HCl ER (1 x 240 mg tablet) and a post-dose confinement period of 12 hours. Subjects will return on Days 16-19 for a morning dose of verapamil HCl ER (1 x 240 mg tablet). Verapamil HCl ER doses administered on Days 15-18 will not necessarily be in a fasted state. On the morning of Day 19 after a fast of at least 10 hours, all study participants will receive co-administered single doses of colchicine (1 x 0.6 mg) and verapamil HCl ER (1 x 240 mg). Fasting will continue for 4 hours following these doses and subjects will be confined to the clinic for dosing and for 24 hours after the dose. Blood samples will be drawn at times sufficient to adequately define the pharmacokinetics of colchicine in the presence of verapamil HCL at steady state. Blood sampling will continue on a non-confined basis on Days 20-23. A further goal of this study is to evaluate the safety and tolerability of this regimen in healthy volunteers. Subjects will be monitored throughout participation in the study for adverse reactions to the study drug and/or procedures. Vital signs (blood pressure and pulse) will be measured pre-dose and 1, 2, and 3 hours post-dose on Day 1, pre-dose and 12 hours post-dose on Day 15, and pre-dose and 1, 2 ,3 and 12 hours post-dose on Day 19 to coincide with peak plasma concentrations of both colchicine and verapamil HCl ER. All adverse events whether elicited by query, spontaneously reported, or observed by clinic staff will be evaluated by the Investigator and reported in the subject's case report form.

Eligibility criteria: Inclusion Criteria:

* Healthy adults 18-45 years of age, non-smoking and non-pregnant (post-menopausal, surgically sterile or using effective contraceptive measures) with a body mass index (BMI) greater than or equal to 18 and less than or equal to 32, inclusive.

Exclusion Criteria:

* Recent participation (within 28 days) in other research studies
* Recent significant blood donation or plasma donation
* Pregnant or lactating
* Test positive at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HbsAg), or hepatitis C virus (HCV)
* Recent (2-year) history or evidence of alcoholism or drug abuse
* History or presence of significant cardiovascular, pulmonary, hepatic, gallbladder or biliary tract, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or psychiatric disease
* Subjects who have used any drugs or substances known to inhibit or induce cytochrome (CYP) P450 enzymes and/or P-glycoprotein (P-gp) within 28 days prior to the first dose and throughout the study
* Drug allergies to colchicine or verapamil

Primary outcomes:
measure: Maximum Plasma Concentration (Cmax)
timeFrame: On Days 1 and 19 - serial pharmacokinetic blood samples were collected pre-dose and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours post-dose.
measure: Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)]
timeFrame: On Days 1 and 19 - serial pharmacokinetic blood samples were collected pre-dose and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours post-dose.
measure: Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]
timeFrame: On Days 1 and 19 - serial pharmacokinetic blood samples were collected pre-dose and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours post-dose.
Secondary outcomes:
Other outcomes:
Locations:
city: East Grand Forks
country: United States
facility: PRACS Institute, Ltd. - Cetero Research
state: Minnesota
Study officials:
affiliation: PRACS - Cetero
name: Anthony R Godfrey, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Terkeltaub RA, Furst DE, Digiacinto JL, Kook KA, Davis MW. Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors. Arthritis Rheum. 2011 Aug;63(8):2226-37. doi: 10.1002/art.30389.