Drug-Drug Interaction Between Colchicine and Ritonavir

A One-Directional, Open-label Drug Interaction Study to Investigate the Effects of Multiple-Dose Ritonavir on Single-Dose Pharmacokinetics of Colchicine in Healthy Volunteers

Ritonavir is a potent inhibitor of CYP3A4, one of the enzymes responsible for the metabolism of colchicine. This study will evaluate the effect of multiple doses of ritonavir 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.

Study Overview

• Status: Completed
• Conditions: Pharmacokinetics
• Intervention / Treatment: Drug: Colchicine; Drug: Colchicine; Drug: Ritonavir

Detailed Description

Ritonavir is a potent inhibitor of CYP3A4, one of the enzymes responsible for the metabolism of colchicine. This study will evaluate the effect of multiple doses of ritonavir 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. 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 a single oral dose of colchicine (1 x 0.6 mg tablet) on Day 1. Fasting will continue for 4 hours after the dose. Blood samples will be drawn from all participants before dosing and for twenty-four 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 study Days 15-18, subjects will return to the clinic daily for non-confined dosing of ritonavir (1 x 100 mg capsule) every 12 hours. Administered ritonavir doses on these days will not necessarily be in a fasted state. On Day 15, after taking the first dose of ritonavir, subjects will remain in the clinic for observation for 1 hour post-dose administration. On day 19 after a fast of at least 10 hours, a single dose of colchicine (1 x 0.6 mg tablet) and ritonavir (1 x 100 mg capsule) will be co-administered to all study participants. Fasting will continue for 4 hours following the co-administered doses of ritonavir and colchicine. All participants will be confined to the clinic for dosing and 24-hour blood sampling at times sufficient to adequately determine the pharmacokinetics of colchicine. Blood sampling will continue on a non-confined basis on Days 20-23. The final dose of ritonavir (1 x 100 mg capsule) will be administered to subjects the evening of Day 19, in a non-fasting state. 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 prior to dosing and at 1, 2, and 3 hours following drug administration on Days 1, 15 and 19 to coincide with peak plasma concentrations of both colchicine and ritonavir. 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.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • East Grand Forks, Minnesota, United States, 56721
      • PRACS Institute, Ltd. - Cetero Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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, hyperlipidemia, pulmonary, hepatic, gallbladder or biliary tract, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurological, 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Colchicine alone; -baseline colchicine pharmacokinetics	Drug: Colchicine; A single dose of colchicine 0.6 mg administered alone at 7:00 a.m. on Day 1 after an overnight fast of at least 10 hours.; Other Names: COLCRYS™; Drug: Colchicine; A single dose of colchicine 0.6 mg administered along with ritonavir at 7:00 a.m. on Day 19
Experimental: Colchicine with Ritonavir; -colchicine pharmacokinetics in presence of steady-state ritonavir	Drug: Colchicine; A single dose of colchicine 0.6 mg administered alone at 7:00 a.m. on Day 1 after an overnight fast of at least 10 hours.; Other Names: COLCRYS™; Drug: Colchicine; A single dose of colchicine 0.6 mg administered along with ritonavir at 7:00 a.m. on Day 19; Drug: Ritonavir; One 100 mg ritonavir capsule administered twice daily at 7:00 a.m. and 7:00 p.m. on Days 15 to 18 without regard to meals, then along with colchicine at 7:00 a.m. on Day 19 after an overnight fast of at least 10 hours; final dose of 100 mg ritonavir administered at 7:00 p.m. on Day 19; Other Names: Norvir® Capsules USP, 100 mg (Abbott Laboratories)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Plasma Concentration (Cmax)	The maximum or peak concentration that colchicine reaches in the plasma.	serial pharmacokinetic blood samples drawn within 1 hour prior to colchicine dosing (0 hour) on Days 1 and 19, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after colchicine dose administration
Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)]	The area under the plasma concentration versus time curve, from time 0 to the time of the last measurable colchicine concentration (t), as calculated by the linear trapezoidal rule.	serial pharmacokinetic blood samples drawn within 1 hour prior to colchicine dosing (0 hour) on Days 1 and 19, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after colchicine dose administration
Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]	The area under the plasma concentration versus time curve from time 0 to infinity. AUC(0-∞) was calculated as the sum of AUC(0-t) plus the ratio of the last measurable colchicine plasma concentration to the elimination rate constant.	serial pharmacokinetic blood samples drawn within 1 hour prior to colchicine dosing (0 hour) on Days 1 and 19, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after colchicine dose administration

Collaborators and Investigators

• Sponsor: Mutual Pharmaceutical Company, Inc.

Publications and helpful links

General Publications

• 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. Erratum In: Arthritis Rheum. 2011 Nov;63(11):3521. Dosage error in article text.

Helpful Links

• Recalls, Market Withdrawals and Safety Alerts
• Daily Med - Posting of Recently Submitted Labeling to the FDA

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (Actual): August 1, 2008
• Study Completion (Actual): August 1, 2008

Study Registration Dates

• First Submitted: August 13, 2009
• First Submitted That Met QC Criteria: August 13, 2009
• First Posted (Estimate): September 24, 2009

Study Record Updates

• Last Update Posted (Estimate): October 15, 2009
• Last Update Submitted That Met QC Criteria: October 12, 2009
• Last Verified: October 1, 2009

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antirheumatic Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Gout Suppressants; Ritonavir; Colchicine
• Other Study ID Numbers: MPC-004-08-1013