Drug-Drug Interaction Study Between Quinine Sulfate and Rosiglitazone

Study Overview
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Brief Summary
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Rosiglitazone is predominantly metabolized by cytochrome P450 (CYP) 2C8. Quinine sulfate is an inhibitor of CYP 2C8. This study will evaluate the effect of multiple doses of quinine sulfate at steady-state on the pharmacokinetics of single-dose rosiglitazone in healthy adult subjects.

Detailed Description
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Rosiglitazone is predominantly metabolized by cytochrome P450 (CYP) 2C8. Quinine sulfate is an inhibitor of CYP 2C8. This study will evaluate the effect of multiple doses of quinine sulfate at steady-state on the pharmacokinetics of single-dose rosiglitazone in healthy adult subjects. On study 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 one oral dose of rosiglitazone (1 x 4 mg tablet). 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 at times sufficient to adequately define the pharmacokinetics of rosiglitazone. A 2 day washout period will be completed after the first dose of rosiglitazone on Day 1. On Days 4-7 all subjects will receive a dose of quinine sulfate (2 x 324 mg capsules) every 8 hours starting with the 7:15 a.m. dose on Day 4 and continuing through the 11:15 p.m. dose on Day 7. Doses of quinine sulfate on Days 4-6 will be administered without regard to meals. On the morning of Day 7 after an overnight fast of at least 10 hours, all study participants will receive co-administered doses of rosiglitazone (1 x 4 mg tablet) and quinine sulfate (2 x 324 mg capsules). 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 at times sufficient to adequately determine the pharmacokinetics of rosiglitazone. 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. Blood pressure (sitting for at least 3 minutes) and pulse will be measured prior to dosing and at 1, 2 and 3 hours after the morning dose of rosiglitazone on Days 1 and 7. Electrocardiograms (EKG) will be recorded on Day 4 before dosing of quinine sulfate and at 1, 2 and 4 hours post-dose and on Day 7 before the co-administered doses of rosiglitazone and quinine sulfate and at 1, 2 and 4 hours post-dose. 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.

Official Title
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An Open-Label Drug-Drug Interaction Study to Investigate the Effects of Steady State Quinine on the Single-Dose Pharmacokinetics of Rosiglitazone Maleate in Healthy Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: Rosiglitazone 4 mg Tablets
* Drug: Rosiglitazone 4 mg Tablets
* Drug: Quinine Sulfate 324 mg Capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adults 18-45 years of age Non-smoking Non-pregnant (post-menopausal, surgically sterile or using effective contraceptive measures) Body mass index (BMI) less than or equal to 32 Medically healthy on the basis of medical history and physical examination Hemoglobin > or = to 11.5g/dL Completion of the screening process within 28 days prior to dosing Provision of voluntary written informed consent 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, pulmonary, hepatic, gallbladder or biliary tract, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, 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 Drug allergies to quinine sulfate or rosiglitazone

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rosiglitazone Alone<br>Baseline rosiglitazone pharmacokinetics. | Drug: Rosiglitazone 4 mg Tablets<br>* Rosiglitazone 4 mg tablet administered as a single oral dose on the morning of Day 1.<br>* Other names: Avandia®;|
| Experimental: Rosiglitazone with Steady State Quinine Sulfate<br>Rosiglitazone pharmacokinetics in the presence of steady state quinine sulfate. | Drug: Rosiglitazone 4 mg Tablets<br>* Co-administered single oral doses of rosiglitazone 4 mg (1 x 4 mg tablet) and quinine sulfate 648 mg (2 x 324 mg capsules) on the morning of Day 7.<br>* Other names: Avandia®;Drug: Quinine Sulfate 324 mg Capsules<br>* Co-administered single oral doses of rosiglitazone 4 mg (1 x 4 mg tablet) and quinine sulfate 648 mg (2 x 324 mg capsules) on the morning of Day 7.<br>* Other names: Qualaquin®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of Rosiglitazone | The maximum or peak concentration that rosiglitazone reaches in the plasma. | serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 7 and then 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 20 and 24 hours after 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 concentration (t), as calculated by the linear trapezoidal rule for rosiglitazone. | serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 7 and then 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 20 and 24 hours after 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 plasma concentration to the elimination rate constant for rosiglitazone. | serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 7 and then 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 20 and 24 hours after dose administration. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rosiglitazone, quinine sulfate, drug interactions, cytochrome p450