Healthy
Conditions
Keywords
midazolam, drug interactions, cytochrome p450
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.
Interventions
DRUGMidazolam Alone
Midazolam 2 mg syrup was given orally after a fast of at least 10 hours.
DRUGQualaquin (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
DRUGMidazolam 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
Sponsors
Mutual Pharmaceutical Company, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Serum Concentration (Cmax) | 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. | 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). | 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 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Qualaquin (Quinine) And Midazolam Alone And In Combination All pharmacokinetic studies were begun after a fast of at least 10 hours. On day 1 all participants received a single oral dose of midazolam 2 mg. Blood was drawn at times sufficient to define the baseline kinetics of midazolam and 1-hydroxy-midazolam. After a 3 day washout period, on the morning of day 4, all participants began a regimen of 324 mg of quinine sulfate orally every 8 hours for a total of 21 doses. On day 9 after taking Qualaquin (quinine) for 5 days according to the stated regimen all participants took their usual dose of Qualaquin (quinine). Blood was drawn sufficient to characterize the steady state kinetics of 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. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Midazolam Alone | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Qualaquin (Quinine) And Midazolam Alone And In Combination |
|---|---|
| Age Continuous | 31.1 years STANDARD_DEVIATION 5.6 |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / — | 27 / — | 4 / — |
| serious Total, serious adverse events | 0 / 24 | 0 / 23 | 0 / 23 |
Outcome results
Primary
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
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
Population: per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam - Midazolam Alone | 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). | 31.324 ng·h/mL | Standard Deviation 10.093 |
| 1-Hydroxy-Midazolam - Midazolam Alone | 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). | 11.669 ng·h/mL | Standard Deviation 7.434 |
| Quinine - Qualaquin(Quinine) Alone | 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). | 28.771 ng·h/mL | Standard Deviation 6.8081 |
| Midazolam - Midazolam With Qualaquin(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). | 11.447 ng·h/mL | Standard Deviation 5.8587 |
Primary
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
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
Population: by protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam - Midazolam Alone | 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. | 30.076 ng•h/mL | Standard Deviation 10.1593 |
| 1-Hydroxy-Midazolam - Midazolam Alone | 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. | 10.780 ng•h/mL | Standard Deviation 6.6534 |
| Quinine - Qualaquin(Quinine) Alone | 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. | 27.242 ng•h/mL | Standard Deviation 6.5008 |
| Midazolam - 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. | 10.454 ng•h/mL | Standard Deviation 5.2714 |
Primary
Maximum Serum Concentration (Cmax)
Maximum serum concentration(Cmax)
Time frame: Day 1 (Midazolam Alone), Day 9 (Qualaquin (quinine) Alone), Day 10 Midazolam with Qualaquin (quinine)
Population: per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam - Midazolam Alone | Maximum Serum Concentration (Cmax) | 12.0435 ng/ml | Standard Deviation 3.53669 |
| 1-Hydroxy-Midazolam - Midazolam Alone | Maximum Serum Concentration (Cmax) | 4.6907 ng/ml | Standard Deviation 2.17605 |
| Quinine - Qualaquin(Quinine) Alone | Maximum Serum Concentration (Cmax) | 4432.4089 ng/ml | Standard Deviation 678.3681 |
| Midazolam - Midazolam With Qualaquin(Quinine) | Maximum Serum Concentration (Cmax) | 12.5585 ng/ml | Standard Deviation 3.5111 |
| 1-Hydroxy-Midazolam -Midazolam With Qualaquin(Quinine) | Maximum Serum Concentration (Cmax) | 4.8605 ng/ml | Standard Deviation 1.82141 |
| Quinine - Qualaquin (Quinine) With Midazolam | Maximum Serum Concentration (Cmax) | 4399.7690 ng/ml | Standard Deviation 671.04523 |
Primary
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.
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
Population: per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Midazolam - Midazolam Alone | The Area Under the the Concentration Time Curve From Zero to Tau (0-8hrs) for Qualaquin (Quinine) AUC Tau Before and After Midazolam | 30455.4 ng•h/mL | Standard Deviation 5028.27 |
| 1-Hydroxy-Midazolam - Midazolam Alone | The Area Under the the Concentration Time Curve From Zero to Tau (0-8hrs) for Qualaquin (Quinine) AUC Tau Before and After Midazolam | 30568.7 ng•h/mL | Standard Deviation 4851.1 |