A One-Directional, Open-Label Drug Interaction Study to Investigate the Effects of Multiple-Dose Diltiazem ER on Single-Dose Pharmacokinetics of Colchicine in Healthy Volunteers
A One-Directional, Open-Label Drug Interaction Study to Investigate the Effects of Multiple-Dose Diltiazem ER on Single-Dose Pharmacokinetics of Colchicine in Healthy Volunteers
Colchicine is a substrate for both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Extended-release diltiazem (diltiazem ER) is a potent inhibitor of both CYP3A4 and P-gp. This study will evaluate the effect of multiple doses of diltiazem 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.
Colchicine is a substrate for both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Extended-release diltiazem (diltiazem ER) is a potent inhibitor of both CYP3A4 and P-gp. This study will evaluate the effect of multiple doses of diltiazem ER on the pharmacokinetic profile of a single 0.6mg dose of colchicine. On 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 a single oral 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 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 at 36, 48, 72, and 96 hours post-dose. After a 14-day washout period, beginning on Day 15 and continuing through Day 20 all subjects will return to the clinic for non-confined dosing of diltiazem ER (1 x 240 mg capsule daily). Administered diltiazem ER doses on these days will not necessarily be in a fasted state. On Day 21 after a fast of at least 10 hours, all study participants will receive a co-administered single oral dose of colchicine (1 x 0.6 mg tablet) and diltiazem ER (1 x 240 mg capsule). 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 in the presence of diltiazem ER at steady state. Blood sampling will then continue on a non-confined basis at 36, 48, 72, and 96 hours post-dose administration. Fasting will continue for 4 hours following the co-administered dose of colchicine and diltiazem ER. 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 at 1, 2, and 3 hours post-dosing on Day 1, pre-dose and 12 hours post-dosing on Day 15 (subjects will return to the study center for the 12-hour post-dose vital sign measurements), and pre-dose and 1, 2, 3 and 12 hours post-dosing on Day 21 to coincide with peak plasma concentrations of both colchicine and diltiazem. 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.
Inclusion Criteria:
Exclusion Criteria: