Drug - Drug Interaction Study of Quinine Sulfate and Ciprofloxacin

Study Overview
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Brief Summary
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Ciprofloxacin is moderate inhibitor of cytochrome P450 1A2 (CYP1A2), one of the enzymes responsible for the metabolism of quinine. This study will evaluate the effect of ciprofloxacin-related inhibition of CYP1A2 on the pharmacokinetics of quinine sulfate.

Detailed Description
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Ciprofloxacin is moderate inhibitor of cytochrome P450 1A2 (CYP1A2), one of the enzymes responsible for the metabolism of quinine. This study will evaluate the effect of ciprofloxacin-related inhibition of CYP1A2 on the pharmacokinetics of quinine sulfate. In the morning 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 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 36 hours post-dose at times sufficient to adequately define the pharmacokinetics of quinine sulfate. A 7-day washout period will be completed after the first dose of quinine sulfate on Day 1. Beginning at 07:45 am on Day 8 and continuing through Day 10, all subjects will return to the clinic for non-confined dosing of ciprofloxacin (1 x 500 mg tablet) every 12 hours. Administered ciprofloxacin doses on these days will not be in a fasted state. At 07:45 am on Day 11 after a fast of at least 10 hours, all study participants will receive a co-administered single oral dose of quinine sulfate (2 x 324 mg capsules) and ciprofloxacin (1 x 500 mg tablet). A final dose of ciprofloxacin (1 x 500 mg tablet) will be administered 12 hours later. Blood samples will be drawn from all participants before dosing and for 36 hours post-dose at times sufficient to adequately define the pharmacokinetics of quinine sulfate. Fasting will continue for 4 hours following the co-administered dose of quinine sulfate and ciprofloxacin. 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 pre-dose and at 1, 2 and 3 hours post-dose on Days 1 and 11. An electrocardiogram (ECG) will be done pre-dose and at 1, 2 and 4 hours post-dose on Days 1 and 11. 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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A One-Directional, Open-Label Drug Interaction Study to Investigate the Effects of Multiple-Dose Ciprofloxacin HCl on the Single-Dose Pharmacokinetics of Quinine in Healthy Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: Quinine Sulfate Capsules 324 mg
* Drug: Ciprofloxacin 500 mg
* Drug: Quinine Sulfate Capsules 324 mg


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)between 18 and 32 Medically healthy on the basis of medical history and physical examination Hemoglobin > or = to 11.5 g/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 mefloquine or quinidine

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: Quinine Sulfate<br>Baseline quinine sulfate pharmacokinetics | Drug: Quinine Sulfate Capsules 324 mg<br>* A single dose of quinine sulfate (2 x 324 mg capsules) administered on the morning of Day 1 after an overnight fast of at least 10 hours.<br>* Other names: Qualaquin®;|
| Experimental: Quinine Sulfate with Ciprofloxacin<br>Quinine sulfate pharmacokinetics in the presence of steady state ciprofloxacin | Drug: Ciprofloxacin 500 mg<br>* A single dose of quinine sulfate (2 x 324 mg capsules) co-administered with a single dose of ciprofloxacin (1 x 500 mg tablet) in the morning on Day 11 after an overnight fast of at least 10 hours.<br>* Other names: Cipro®;Drug: Quinine Sulfate Capsules 324 mg<br>* A single dose of quinine sulfate (2 x 324 mg capsules) co-administered with a single dose of ciprofloxacin (1 x 500 mg tablet) in the morning on Day 11 after an overnight fast of at least 10 hours.<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) | The maximum or peak concentration that the drug reaches in the plasma. | Serial pharmacokinetic blood samples for quinine sulfate collected on Days 1 and 11 before dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 and 36 hours post-dose. | 
| 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 beginning from the first dose (time 0) to the last measurable concentration (time t), as calculated by the linear trapezoidal method. | Serial pharmacokinetic blood samples for quinine sulfate collected on Days 1 and 11 before dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 and 36 hours post-dose. | 
| Area Under the Concentration 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 the AUC(0-t) plus the ratio of the last measurable plasma concentration to the elimination rate constant. | Serial pharmacokinetic blood samples for quinine sulfate collected on Days 1 and 11 before dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 and 36 hours post-dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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quinine sulfate, ciprofloxacin, drug interactions, cytochrome p450, male, female, adult, pharmacokinetics