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Drug-Drug Interaction Study of Qualaquin and Midazolam

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ClinicalTrials.gov Identifier: NCT00785486
Recruitment Status : Completed
First Posted : November 5, 2008
Results First Posted : July 8, 2009
Last Update Posted : August 31, 2012
Sponsor:
Information provided by (Responsible Party):
Mutual Pharmaceutical Company, Inc.

Tracking Information
First Submitted Date  ICMJE November 4, 2008
First Posted Date  ICMJE November 5, 2008
Results First Submitted Date March 11, 2009
Results First Posted Date July 8, 2009
Last Update Posted Date August 31, 2012
Study Start Date  ICMJE March 2007
Actual Primary Completion Date March 2007   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 22, 2012)
  • Maximum Serum Concentration (Cmax) [ Time Frame: Day 1 (Midazolam Alone), Day 9 (Qualaquin (quinine) Alone), Day 10 Midazolam with Qualaquin (quinine) ]
    Maximum serum concentration(Cmax)
  • Area Under the Concentration Time Curve From Zero to T (AUC 0-t) for Midazolam and 1-hydroxy Midazolam at Baseline and With Qualaquin (Quinine) at Steady State. [ Time Frame: Days 1 and 10 at 0.167, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 7.917, 12, 15 and 24 hours ]
    Area under the concentration time curve(AUC 0-t) calculated by the linear trapezoidal method from time 0 to 24 hours, for Midazolam and 1-hydroxy-midazolam on day 1 (midazolam alone) and day 10 (midazolam with Qualaquin -(quinine) at steady state to determine if a significant drug interaction occurs between midazolam and quinine
  • Area Under the Concentration Time Curve From Zero to Infinity (AUC Inf) for Midazolam and 1 Hydroxy Midazolam Before (Day 1) and After (Day 10) Qualaquin (Quinine). [ Time Frame: Days 1 and 10 at 0.167, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 7.917, 12, 15 and 24 hours ]
    AUC inf for Midazolam and hydroxy-midazolam on day 1 (midazolam alone) and day 10 (midazolam with steady state Qualaquin(quinine)- the sum of AUC0-t plus the ratio of the last measured plasma concentration to the elimination rate constant to determine whether a significant drug interaction occurs between midazolam and quinine
  • The Area Under the the Concentration Time Curve From Zero to Tau (0-8hrs) for Qualaquin (Quinine) AUC Tau Before and After Midazolam [ Time Frame: Days 9 and 10 at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, and 7.917 hours ]
    Qualaquin (quinine) - AUC tau alone at steady state (day 9) and in the presence of coadministered midazolam 2 mg (day 10) over the dosing interval (0 - 8 hours), as calculated by the linear trapezoidal method.
Original Primary Outcome Measures  ICMJE
 (submitted: November 4, 2008)
90% confidence interval of ratios of least-squares means for the Ln transformed kinetic parameters of midazolam and its 1-hydroxy metabolite before and after quinine at steady state, and quinine at steady state before and after midazolam [ Time Frame: days 1 and 10 ]
Change History Complete list of historical versions of study NCT00785486 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: November 4, 2008)
For informational purposes: 1 hydroxy-midazolam /midazolam ratios for AUC, Cmax and Tmax,;the least squares means for relevant PK parameters for quinine for day 4 (initial dose) vs. day 9 (steady state) will also be presented [ Time Frame: Days 1, 4, 9 and 10 ]
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE Drug-Drug Interaction Study of Qualaquin and Midazolam
Official Title  ICMJE A Pharmacokinetic Interaction Study Evaluating the Effect of Qualaquin (Quinine Sulfate) Capsules on Midazolam
Brief Summary This is an open label non-randomized single sequence, single group two way drug interaction study in healthy adult volunteers to determine the extent to which quinine, an inducer of cytochrome p450 CYP 3A4, affects the pharmacokinetics of midazolam, an accepted probe drug for CYP 3A4. The study will also determine the extent to which midazolam affects the pharmacokinetics of quinine.
Detailed Description This is an open label single sequence single group non-randomized two way drug interaction study in healthy adult volunteers to determine the extent to which quinine, an inducer of cytochrome p450 CYP 3A4, affects the pharmacokinetics of midazolam, an accepted probe drug for CYP 3A4. The study will also determine the extent to which midazolam affects the pharmacokinetics of quinine. This will compare the pharmacokinetics of midazolam and quinine at baseline to their kinetics when they are taken together in 24 normal healthy adult volunteers who will serve as their own controls. All patients will be confined to the study site throughout the entire 11 day study period. On day 1 after a fast of at least 10 hours, all study participants will receive a single oral dose of midazolam 2 mg. Blood will be drawn at times sufficient to adequately define the baseline concentration time curve for midazolam and its metabolite, 1-hydroxy-midazolam. On the morning of day 4, after a 3 day washout period and following a fast of at least 10 hours, all volunteers will begin a regimen of 324 mg of quinine sulfate by mouth every 8 hours. All subjects will continue this regimen from day 4-10 (21 total doses). Blood will be drawn after the first daily dose of quinine on days 4 and 9 at times sufficient to adequately define the baseline and steady state concentration time curves for quinine. Additional blood will be drawn prior to the first daily dose of quinine on days 7,8,9,and 10. On day 10 after a fast of at least a 10 hours, all participants will receive both midazolam 2 mg and quinine 324 mg together. Blood will be drawn a times sufficient to characterize the pharmacokinetics of midazolam, 1-hydroxy-midazolam and quinine under the stated conditions.
Study Type  ICMJE Interventional
Study Phase Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Healthy
Intervention  ICMJE
  • Drug: Midazolam Alone
    Midazolam 2 mg syrup was given orally after a fast of at least 10 hours.
    Other Name: Midazolam
  • Drug: Qualaquin (quinine) alone steady state
    Qualaquin (quinine) 324 mg capsules were given orally every 8 hours for 7 days ( 21 doses total). On day 9 after taking Qualaquin (quinine) for 5 days according to the stated regimen and fasting for at least 10 hours, all participants took their usual dose of Qualaquin (quinine). Blood was drawn at times sufficient to characterize the pharmacokinetics of quinine at steady state
    Other Name: Qualaquin, Quinine Sulfate
  • Drug: Midazolam and Qualaquin at steady state
    On the morning of day 10 after taking Qualaquin (quinine) for 6 days according to the stated regimen (324 mg every 8 hours), all participants took their usual dose of Qualaquin (quinine) with an oral dose of midazolam 2 mg after a fast of at least 10 hours
    Other Name: midazolam, Qualaquin, quinine sulfate
Study Arms
  • Midazolam alone
    Baseline midazolam and 1-hydroxy-midazolam pharmacokinetics. One day 1 after a fast of at least 10 hours patients received a single oral dose of midazolam 2 mg. Blood was drawn at times sufficient to characterize the pharmacokinetics of midazolam and its main metabolite.
    Intervention: Drug: Midazolam Alone
  • Qualaquin (quinine) alone steady state
    On the morning of day 9 after taking Qualaquin (quinine) capsules 324 mg orally every 8 hours for the prior 5 days, and following a fast of at least 10 hours all study participants received their usual morning dose of Qualaquin (quinine) 324 mg. Blood was drawn at times sufficient to determine the steady state Cmax and AUC 0-tau for Qualaquin (quinine).
    Intervention: Drug: Qualaquin (quinine) alone steady state
  • Experimental: Midazolam with Qualaquin (quinine)
    On day 10 after taking Qualaquin (quinine) for 6 days according to the stated regimen, all participants took their usual dose of Qualaquin (quinine) with an oral dose of midazolam 2 mg. Blood was drawn sufficient to characterize the steady state kinetics of quinine and the kinetics of midazolam and 1-hydroxy-midazolam in the presence of each other.
    Intervention: Drug: Midazolam and Qualaquin at steady state
Publications * Terkeltaub RA, Furst DE, Digiacinto JL, Kook KA, Davis MW. Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors. Arthritis Rheum. 2011 Aug;63(8):2226-37. doi: 10.1002/art.30389. Erratum in: Arthritis Rheum. 2011 Nov;63(11):3521. Dosage error in article text.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 4, 2008)
24
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date March 2007
Actual Primary Completion Date March 2007   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Medically healthy non-smoking, non-obese (≥ 60 kg males, ≥52 kg females within 15% of IBW) adult volunteers 18-45 years of age

Exclusion Criteria:

  • Subjects with history or presence of significant cardiovascular disease (including hypotension, hypertension, 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 10 days or 28 days respectively prior to the first dose and throughout the study.
  • Subjects who have received monoamine oxidase inhibitors or been on a special diet within 28 days of starting 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, taking hormone replacement therapy or have known allergies to quinine sulfate, mefloquine, quinidine or midazolam and other benzodiazepines.

Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00785486
Other Study ID Numbers  ICMJE MPC-001-07-1001
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Mutual Pharmaceutical Company, Inc.
Study Sponsor  ICMJE Mutual Pharmaceutical Company, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Matthew Davis, MD Mutual Pharmaceutical
Principal Investigator: Dennis Swearingen, MD MDS Pharma Services
PRS Account Mutual Pharmaceutical Company, Inc.
Verification Date August 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP