Drug-Drug Interaction Study of Qualaquin and Midazolam

NCT00785486 | Completed Phase 1 Results

• 1 other identifier: MPC-001-07-1001
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy

Keywords

midazolam; drug interactions; cytochrome p450

Outcome Measures

Primary Outcomes (4)

• Maximum Serum Concentration (Cmax)

  Maximum serum concentration(Cmax)

  Day 1 (Midazolam Alone), Day 9 (Qualaquin (quinine) Alone), Day 10 Midazolam with Qualaquin (quinine)

• 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.

  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

  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 From Zero to Infinity (AUC Inf) for Midazolam and 1 Hydroxy Midazolam Before (Day 1) and After (Day 10) Qualaquin (Quinine).

  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

  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

• The Area Under the the Concentration Time Curve From Zero to Tau (0-8hrs) for Qualaquin (Quinine) AUC Tau Before and After Midazolam

  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.

  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

Study Arms (3)

Midazolam alone

OTHER

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

Qualaquin (quinine) alone steady state

OTHER

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

Midazolam with Qualaquin (quinine)

EXPERIMENTAL

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

Interventions

Midazolam Alone DRUG

Midazolam 2 mg syrup was given orally after a fast of at least 10 hours.

Also known as: Midazolam

Midazolam alone

Qualaquin (quinine) alone steady state DRUG

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

Also known as: Qualaquin, Quinine Sulfate

Qualaquin (quinine) alone steady state

Midazolam and Qualaquin at steady state DRUG

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

Also known as: midazolam, Qualaquin, quinine sulfate

Midazolam with Qualaquin (quinine)

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Mutual Pharmaceutical Company, Inc.: lead

Study Sites (1)

MDS Pharma Services

Phoenix, Arizona, 85044, United States

Location

Related Publications (1)

• 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.

  PMID: 21480191 DERIVED

Related Links

• Recalls, Market Withdrawals and Safety Alerts
• Daily Med - Posting of Recently Submitted Labeling to the FDA

MeSH Terms

Interventions

Midazolam; Quinine

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Cinchona Alkaloids; Alkaloids; Quinuclidines; Heterocyclic Compounds, Bridged-Ring; Quinolines

Results Point of Contact

• Title: Medical Affairs Director
• Organization: Mutual Pharmaceutical Company, Inc.

clinicaltrials@urlmutual.com

215-697-1743

Study Officials

• Matthew Davis, MD

  Mutual Pharmaceutical

  STUDY CHAIR

• Dennis Swearingen, MD

  MDS Pharma Services

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 4, 2008
• First Posted: November 5, 2008
• Study Start: March 1, 2007
• Primary Completion: March 1, 2007
• Study Completion: March 1, 2007
• Last Updated: August 31, 2012
• Results First Posted: July 8, 2009

Record last verified: 2012-08

Locations

US (1)