Drug - Drug Interaction Study Between Quinine Sulfate and Theophylline
Condition: Pharmacokinetics
Study type: Interventional
Phase: Phase 1

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.
    

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.
    

Intervention name(s): Theophylline 300mg; Quinine 648 mg; Theophylline 300 mg; Quinine 648 mg
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Single doses of theophylline 300 mg as an immediate-release oral solution 80mg/15ml concentration administered alone at 7 am on Day 1 after an overnight fast of at least 10 hours and along with quinine sulfate (2 x 324 mg capsules) at 7am on Day 12 after an overnight fast of at least 10 hours.; 648 mg quinine sulfate(2 x 324 mg capsules) initiated at 3pm on Day 5 and taken every 8 hours through Day 11 and co-administered with theophylline 300 mg as an immediate-release oral solution 80 mg/15 ml concentration at 7am on Day 12.; Single doses of theophylline 300 mg as an immediate-release oral solution 80mg/15ml concentration administered alone at 7 am on Day 1 after an overnight fast of at least 10 hours and along with quinine sulfate (2 x 324 mg capsules) at 7am on Day 12 after an overnight fast of at least 10 hours.; 648 mg quinine sulfate(2 x 324 mg capsules) initiated at 3pm on Day 5 and taken every 8 hours through Day 11 and co-administered with theophylline 300 mg as an immediate-release oral solution 80 mg/15 ml concentration at 7am on Day 12.
Intervention MeSH terms: Quinine; Theophylline
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: quinine sulfate; theophylline; drug interactions; cytochrome p450; humans; male; adult