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

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.