Drug-Drug Interaction Study of Colchicine and Theophylline

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

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. A secondary goal is to evaluate the safety and tolerability of this regimen in healthy volunteers. All study subjects will be monitored for adverse events throughout the entire study period.

Study Overview

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

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Dakota
    • Fargo, North Dakota, United States, 58104
      • PRACS Institute, Ltd. - Cetero Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy adults 18-45 years of age, non-smoking and non-pregnant (postmenopausal, 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 donation of plasma
• 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, hematological, 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: Theophylline alone; baseline theophylline kinetics	Drug: Theophylline; single doses of 300 mg (80 mg/15 ml elixer) administered alone at 7:45 am on Day 1 and then along with colchicine at 7:45 am on Day 19; Other Names: Elixophyllin® Elixir (Theophylline Anhydrous) 80/15 ml concentrate
Experimental: Theophylline with steady-state Colchicine; theophylline pharmacokinetics upon administration with colchicine at steady-state	Drug: Theophylline; single doses of 300 mg (80 mg/15 ml elixer) administered alone at 7:45 am on Day 1 and then along with colchicine at 7:45 am on Day 19; Other Names: Elixophyllin® Elixir (Theophylline Anhydrous) 80/15 ml concentrate; Drug: Colchicine; one 0.6 mg tablet twice daily at 7:45 am and 7:45 pm on Days 5 to 19

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Plasma Concentration (Cmax)	The maximum or peak concentration that theophylline drug reaches in the plasma.	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
Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)]	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.	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
Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]	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.	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

Collaborators and Investigators

• Sponsor: Mutual Pharmaceutical Company, Inc.

Publications and helpful links

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: August 1, 2008
• Primary Completion (Actual): September 1, 2008
• Study Completion (Actual): September 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): March 2, 2010
• Last Update Submitted That Met QC Criteria: February 23, 2010
• Last Verified: February 1, 2010

More Information

Terms related to this study

• Keywords: healthy;; adult;; blood levels over time
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Antirheumatic Agents; Purinergic Antagonists; Purinergic Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Gout Suppressants; Theophylline; Colchicine
• Other Study ID Numbers: MPC-004-08-1010