Drug-Drug Interaction Study Between Colchicine and Atorvastatin

• Maximum Plasma Concentration (Cmax) of Colchicine [ Time Frame: serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 28 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after dose administration. ] [ Designated as safety issue: No ]
  The maximum or peak concentration that colchicine reaches in the plasma.
  
  
• Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] [ Time Frame: Serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 28 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after dose administration. ] [ Designated as safety issue: No ]
  The area under the plasma concentration versus time curve from time 0 to the time of the last measurable concentration (t), as calculated by the linear trapezoidal rule for colchicine.
  
  
• Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] [ Time Frame: Serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 28 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after dose administration. ] [ Designated as safety issue: No ]
  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 plasma concentration to the elimination rate constant for colchicine.
  
  

Colchicine is a substrate for cytochrome P450 3A4 (CYP3A4). In-vitro studies have indicated that the ortho-and para-hydroxylated metabolites of atorvastatin may be CYP3A4 /5 competitive and mechanism-based inhibitors (MBI). This study will evaluate the effect of multiple doses of atorvastatin on the pharmacokinetic profile of a single 0.6 mg dose of colchicine. Twenty-four healthy, non-smoking, non-obese, non-pregnant adult volunteers between the ages of 18 and 45 will be given one oral dose of colchicine (1 x 0.6 mg tablet) on Day 1 after an overnight fast. Blood samples will be drawn from all participants before dosing and for 24 hours post-dose at times sufficient to adequately define the pharmacokinetics of colchicine. After a 14 day washout period, starting on the morning of Day 15 and continuing through Day 27, subjects will return to the clinic for once daily administration of atorvastatin (1 x 40 mg tablet) after an overnight fast. After taking the first dose of atorvastatin on Day 15, subjects will remain in the clinic for 1 hour post-dose administration for observation. On the morning of Day 28 after an overnight fast, all study participants will receive a co-administered single oral dose of colchicine (1 x 0.6 mg tablet) and atorvastatin (1 x 40 mg tablet). Blood samples will be drawn from all participants before dosing and for twenty-four hours post-dose at times sufficient to adequately define the pharmacokinetics of colchicine in the presence of atorvastatin at steady 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. Seated blood pressure and pulse, respiratory rate and temperature will be measured at screening, baseline and upon study discharge. Blood pressure and pulse will also be measured pre-dose and at 1 and 2 hours post-dose on Days 1 and 28 to coincide with peak plasma concentrations of colchicine and atorvastatin. 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.