Drug - Drug Interaction Study Between Quinine Sulfate and Theophylline
Information source: Mutual Pharmaceutical Company, Inc.
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Pharmacokinetics
Intervention: Theophylline 300mg (Drug); Quinine 648 mg (Drug); Theophylline 300 mg (Drug); Quinine 648 mg (Drug)
Phase: Phase 1
Status: Completed
Sponsored by: Mutual Pharmaceutical Company, Inc. Official(s) and/or principal investigator(s): Matthew Davis, MD, Study Chair, Affiliation: Mutual Pharmaceutical Barrie March, MD, Principal Investigator, Affiliation: PRACS Institute
Summary
In a prior in vitro study using human hepatocytes quinine was shown to induce the activity
of Cytochrome p450 CYP 1A2. The present study will evaluate the extent to which quinine
sulfate-related induction of this enzyme effects the pharmacokinetics of theophylline, a
sensitive probe drug for the activity of CYP 1A2. It will also evaluate the effect of
single-dose theophylline on the pharmacokinetics of steady-state quinine sulfate.
Clinical Details
Official title: A Pharmacokinetic Drug-Drug Interaction Study to Evaluate the Effect of Steady-State Quinine Sulfate on the Pharmacokinetics of Single-Dose Theophylline in Healthy Adult Males
Study design: Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science
Primary outcome: Maximum Plasma Concentration(Cmax)Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)].
Secondary outcome: Electrocardiogram (ECG) Evaluation of the Maximum QT Interval Corrected for Heartrate (QTc), Quinine Study Day 11.Electrocardiogram (ECG) Evaluation of the Maximum QT Interval Corrected for Heartrate (QTc), Theophylline Co-administered With Quinine, Study Day 12.
Detailed description:
This study will evaluate the effect of steady-state quinine sulfate on the pharmacokinetics
of single dose theophylline and the effect of single dose theophylline on the
pharmacokinetics of steady-state quinine sulfate in healthy adult males under fasting
conditions. In this non-blinded, crossover study 24 normal, healthy, non-smoking, non-obese
male volunteers will serve as their own controls in two cohorts, one consisting of 8
subjects and one consisting of 16 subjects. On Day 1 after a minimum overnight fast of 10
hours, the 8 study participants in cohort 1 will receive a single oral dose of theophylline
(300 mg as an immediate-release oral solution 80 mg/ 15 ml concentration). After a 4 day
washout period, the 8 subjects will receive a 648 mg dose of quinine sulfate (2 x 324 mg
capsules) every 8 hours (dosing at 7 am, 3 pm and 11 pm daily) beginning with the 3 pm dose
on Day 5 and continuing through the morning dose on Day 12. The 8 subjects will be
co-administered single oral doses of theophylline (300 mg as an immediate-release oral
solution 80 mg/ 15 ml concentration) and quinine sulfate (2 x 324 mg capsules) at 7 am on
Day 12. Cohort 2 will be dosed on the basis of safety findings in Cohort 1. If ≥ 50% of
the volunteers in cohort 1 do not tolerate the 648 mg dose of quinine sulfate, the second
cohort of 16 volunteers will receive a dose of quinine sulfate reduced from 648 mg to 324 mg
every 8 hours. In each cohort serial pharmacokinetic blood samples will be drawn at times
sufficient to adequately define the pharmacokinetics of theophylline and quinine. Blood
samples for the measurement of theophylline plasma concentrations will be collected on Days
1 and 12 prior to dosing and at 0. 5, 1, 1. 5, 2, 2. 5, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours
post-dose. Blood samples for the measurement of quinine sulfate plasma concentrations will
be collected on Day 11 prior to the morning dose and at 0. 5, 1, 1. 5, 2, 2. 5, 3, 4, 6, and 8
hours post dose and on Day 12 prior to dosing and at 0. 5, 1, 1. 5, 2, 2. 5, 3, 4, 6 and 8
hours post-dose. 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. Vital signs (sitting
blood pressure and pulse) will be measured prior to the morning dose and at 1, 2 and 4 hours
after administration of the morning dose on Days 1, 11 and 12. On Day 5, sitting blood
pressure and pulse will be measured prior to the afternoon dose and at 1, 2 and 4 hours
after administration of the afternoon dose. ECGs will be collected pre-dose and at 4 hours
after the morning dose on study Days 1, 5, 11 and 12. 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.
Eligibility
Minimum age: 18 Years.
Maximum age: 45 Years.
Gender(s): Male.
Criteria:
Inclusion Criteria:
- Medically healthy non-smoking, non-obese (≥ 55kg and within 15% of ideal body weight)
adult male volunteers 18-45 years of age
Exclusion Criteria:
- Subjects with history or presence of glucose 6 phosphate dehydrogenase deficiency,
myasthenia gravis, optic neuritis, glaucoma or significant cardiovascular disease
(including hypotension, bradycardia or EKG abnormalities), pulmonary, hepatic,
gallbladder or biliary tract, renal, hematologic, gastrointestinal, endocrine,
immunologic, dermatologic, neurologic, psychiatric disease or an active sexually
transmitted disease
- Subjects with significant blood loss in the prior 56 days, plasma donation within 7
days , hemoglobin <12. 0 g/dl or who have participated in another clinical trial
within the prior 30 days
- Subjects with recent (2-year) history or evidence of alcoholism or drug abuse
- Subjects who have used any drugs or substances known to inhibit or induce cytochrome
P450 (CYP) enzymes and/or P-glycoprotein within 30 days prior to the first dose and
throughout the study
- Subjects who test positive at screening for human immunodeficiency virus (HIV),
hepatitis B surface antigen (HbsAg), or hepatitis C virus (HCV).
- Subjects who are pregnant or lactating or have hypersensitivity to quinine sulfate,
mefloquine, quinidine or hypersensitivity to theophylline or aminophylline.
Locations and Contacts
PRACS Institute, Fargo, North Dakota 58104, United States
Additional Information
Starting date: August 2007
Last updated: October 20, 2009
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