Drug-Drug Interaction Study of Colchicine and Theophylline

• Maximum Plasma Concentration (Cmax) [ Time Frame: serial pharmacokinetic blood samples drawn within 1 hour prior to theophylline dosing (0 hour) on Days 1 and 19, then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after theophylline dose administration ] [ Designated as safety issue: No ]
  The maximum or peak concentration that theophylline drug 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 within 1 hour prior to theophylline dosing (0 hour) on Days 1 and 19, then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after theophylline dose administration ] [ Designated as safety issue: No ]
  The area under the theophylline plasma concentration versus time curve, from time 0 to the time of the last measurable theophylline concentration (t), as calculated by the linear trapezoidal rule.
  
  
• Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] [ Time Frame: serial pharmacokinetic blood samples drawn within 1 hour prior to theophylline dosing (0 hour) on Days 1 and 19, then at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, and 48 hours after theophylline dose administration ] [ Designated as safety issue: No ]
  The area under the theophylline 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 theophylline plasma concentration to the elimination rate constant.
  
  

Colchicine is a supressor of hepatic CYP1A2 and theophylline is a sensitive CYP1A2 probe substrate. When the two are co-administered the potential exists for a clinically significant drug interaction . This study aims to determine the effect of steady-state colchicine on the pharmacokinetics of theophylline administered as a single dose. After a fast of at least 10 hours, thirty healthy, non-smoking, non-obese, non-pregnant adult volunteers between the ages of 18 and 45 will be given one dose of 300mg (80mg/15ml concentrate) theophylline (theophylline elixir) on Day 1. 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 determine the pharmacokinetics of theophylline. Blood sampling will then continue on a non-confined basis on days 2-3. A four day washout period will be completed after the theophylline dose on Day 1 and prior to administration of the first colchicine dose on Day 5. Participants will return to the clinic on days 5-18 for non-confined dosing of colchicine (0.6mg every 12 hours). Administered dosing on these days will not necessarily be in a fasted state.

On Day 19 after a fast of at least 10 hours, all study participants will receive 300mg theophylline (80mg/15ml) and 0.6 mg colchicine (1 x 0.6mg tablet) together. Fasting will continue for 4 hours following these co-administered doses. All subjects will be confined to the clinic for dosing and the following 24-hour period. Blood samples will be drawn at times sufficient to adequately determine the pharmacokinetics of theophylline in the presence of colchicine at steady state. Blood sampling will continue on a non-confined basis on Days 20-21. The final dose of colchicine (1x0.6mg) will be administered to subjects the evening of Day 19.

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 will be measured prior to dosing and at approximately 1, 2, and 3 hours following drug administration on Days 1, 5 (after the morning dose) and 19. 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.