Drug-Drug Interaction Study of Qualaquin and Midazolam

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Mutual Pharmaceutical Company, Inc.
ClinicalTrials.gov Identifier:
NCT00785486
First received: November 4, 2008
Last updated: August 22, 2012
Last verified: August 2012
  Purpose

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.


Condition Intervention Phase
Healthy
Drug: Midazolam Alone
Drug: Qualaquin (quinine) alone steady state
Drug: Midazolam and Qualaquin at steady state
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: A Pharmacokinetic Interaction Study Evaluating the Effect of Qualaquin (Quinine Sulfate) Capsules on Midazolam

Resource links provided by NLM:


Further study details as provided by Mutual Pharmaceutical Company, Inc.:

Primary Outcome Measures:
  • Maximum Serum Concentration (Cmax) [ Time Frame: Day 1 (Midazolam Alone), Day 9 (Qualaquin (quinine) Alone), Day 10 Midazolam with Qualaquin (quinine) ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.


Enrollment: 24
Study Start Date: March 2007
Study Completion Date: March 2007
Primary Completion Date: March 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Midazolam Alone
Midazolam 2 mg syrup was given orally after a fast of at least 10 hours.
Other Name: Midazolam
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).
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
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.
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

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.

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00785486

Locations
United States, Arizona
MDS Pharma Services
Phoenix, Arizona, United States, 85044
Sponsors and Collaborators
Mutual Pharmaceutical Company, Inc.
Investigators
Study Chair: Matthew Davis, MD Mutual Pharmaceutical
Principal Investigator: Dennis Swearingen, MD MDS Pharma Services
  More Information

Additional Information:
No publications provided by Mutual Pharmaceutical Company, Inc.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Mutual Pharmaceutical Company, Inc.
ClinicalTrials.gov Identifier: NCT00785486     History of Changes
Other Study ID Numbers: MPC-001-07-1001
Study First Received: November 4, 2008
Results First Received: March 11, 2009
Last Updated: August 22, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Mutual Pharmaceutical Company, Inc.:
midazolam
drug interactions
cytochrome p450

Additional relevant MeSH terms:
Midazolam
Quinine
Adjuvants, Anesthesia
Analgesics
Analgesics, Non-Narcotic
Anesthetics
Anesthetics, General
Anesthetics, Intravenous
Anti-Anxiety Agents
Anti-Infective Agents
Antimalarials
Antiparasitic Agents
Antiprotozoal Agents
Central Nervous System Agents
Central Nervous System Depressants
GABA Agents
GABA Modulators
Hypnotics and Sedatives
Molecular Mechanisms of Pharmacological Action
Muscle Relaxants, Central
Neuromuscular Agents
Neurotransmitter Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Psychotropic Drugs
Sensory System Agents
Therapeutic Uses
Tranquilizing Agents

ClinicalTrials.gov processed this record on October 30, 2014