Pharmacokinetics
Conditions
Keywords
quinine sulfate, theophylline, drug interactions, cytochrome p450, humans, male, adult
Brief 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.
Interventions
DRUGTheophylline 300mg
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.
DRUGQuinine 648 mg
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.
Sponsors
Mutual Pharmaceutical Company, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Medically healthy non-smoking, non-obese (≥ 55kg and within 15% of ideal body weight) adult male volunteers 18-45 years of age
Exclusion criteria
* Subjects with history or presence of glucose 6 phosphate dehydrogenase deficiency, myasthenia gravis, optic neuritis, glaucoma or significant cardiovascular disease (including hypotension, 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 and/or P-glycoprotein within 30 days prior to the first dose and throughout 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 or have hypersensitivity to quinine sulfate, mefloquine, quinidine or hypersensitivity to theophylline or aminophylline.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration(Cmax) | Serial pharmacokinetic blood samples for theophylline collected on Days 1 and 12 before dosing and for 48 hours post-dose. Serial pharmacokinetic blood samples for quinine collected on Days 11 and 12 before dosing and for 8 hours after the morning dose. | The maximum or peak concentration that the drug reaches in the plasma. |
| Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | Serial pharmacokinetic blood samples for theophylline collected on Days 1 and 12 before dosing and for 48 hours post-dose. Serial pharmacokinetic blood samples for quinine collected on Days 11 and 12 before dosing and for 8 hours after the morning dose. | The area under the plasma concentration versus time curve beginning from the first dose (time 0) to the last measurable concentration (time t), as calculated by the linear trapezoidal method. |
| Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]. | Serial pharmacokinetic blood samples for theophylline collected on Days 1 and 12 before dosing and for 48 hours post-dose. | The area under the plasma concentration versus time curve from time 0 to infinity. AUC(0-∞)was calculated as the sum of the AUC(0-t) plus the ratio of the last measurable plasma concentration to the elimination rate constant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Electrocardiogram (ECG) Evaluation of the Maximum QT Interval Corrected for Heartrate (QTc), Theophylline Co-administered With Quinine, Study Day 12. | 5 hours - measured 1 hour pre-dose and then at 4 hours post-dose on Day 12 | The QT interval assesses cardiac repolarization and risk for arrhythmias. It is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. QTc is the QT interval corrected for heartrate. |
| Electrocardiogram (ECG) Evaluation of the Maximum QT Interval Corrected for Heartrate (QTc), Quinine Study Day 11. | 5 hours - measured 1 hour pre-dose and then at 4 hours after the morning dose on Day 11 | The QT interval assesses cardiac repolarization and risk for arrhythmias. It is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. QTc is the QT interval corrected for heartrate. |
Countries
United States
Participant flow
Recruitment details
Twenty-four (24) healthy, non-smoking, adult male volunteers from the community at large were enrolled.
Pre-assignment details
Fifty-two (52) subjects were screened. Ten (10) were screen failures, eight (8) did not return and ten (10) were discharged.
Participants by arm
| Arm | Count |
|---|---|
| Theophylline Alone, Quinine Alone, Theophylline With Quinine This study was done in two cohorts, each receiving the same dosing regimen. For each cohort, all subjects received a single dose of theophylline (300 mg as an immediate-release oral solution 80 mg/15 ml concentration) at 7:00am on Day 1 following an overnight fast of at least 10 hours. After a 4-day washout period, subjects received 648 mg of quinine sulfate (2 x 324 mg capsules) every 8 hours (dosing occurred at 7am, 3pm and 11pm daily) starting with the 3pm dose on Day 5 and continuing through the morning dose on Day 12. Subjects also received a single 300 mg dose of theophylline along with their 648 mg quinine sulfate dose on the morning of Day 12. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Quinine Alone | Adverse Event | 2 |
Baseline characteristics
| Characteristic | Theophylline Alone, Quinine Alone, Theophylline With Quinine |
|---|---|
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants |
| Age Continuous | 27.25 years STANDARD_DEVIATION 6.038 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 24 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 | 7 / — | 22 / — | 20 / — |
| serious Total, serious adverse events | 0 / — | 1 / — | 0 / — |
Outcome results
Primary
Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)].
The area under the plasma concentration versus time curve from time 0 to infinity. AUC(0-∞)was calculated as the sum of the AUC(0-t) plus the ratio of the last measurable plasma concentration to the elimination rate constant.
Time frame: Serial pharmacokinetic blood samples for theophylline collected on Days 1 and 12 before dosing and for 48 hours post-dose.
Population: A total of 24 healthy adult male subjects participated in this study, 22 of whom completed. Pharmacokinetic analyses of theophylline are based on 19 subjects (data for 2 subjects excluded due to vomiting post-dose and for 1 subject as an outlier. Pharmacokinetic analyses of quinine are based on 20 subjects (excluding the two who vomited).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Theophylline Alone | Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]. | 108.21 ug-hr/mL | Standard Deviation 37.33 |
| Quinine Alone | Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]. | 96.88 ug-hr/mL | Standard Deviation 31.95 |
Primary
Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)]
The area under the plasma concentration versus time curve beginning from the first dose (time 0) to the last measurable concentration (time t), as calculated by the linear trapezoidal method.
Time frame: Serial pharmacokinetic blood samples for theophylline collected on Days 1 and 12 before dosing and for 48 hours post-dose. Serial pharmacokinetic blood samples for quinine collected on Days 11 and 12 before dosing and for 8 hours after the morning dose.
Population: A total of 24 healthy adult male subjects participated in this study, 22 of whom completed. Pharmacokinetic analyses of theophylline are based on 19 subjects (data for 2 subjects excluded due to vomiting post-dose and for 1 subject as an outlier. Pharmacokinetic analyses of quinine are based on 20 subjects (excluding the two who vomited).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Theophylline Alone | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 103.47 ug-hr/mL | Standard Deviation 35.82 |
| Quinine Alone | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 45.17 ug-hr/mL | Standard Deviation 11.41 |
| Theophylline in the Presence of Quinine | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 92.72 ug-hr/mL | Standard Deviation 31.17 |
| Quinine in the Presence of Theophylline | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 51.68 ug-hr/mL | Standard Deviation 13.11 |
Primary
Maximum Plasma Concentration(Cmax)
The maximum or peak concentration that the drug reaches in the plasma.
Time frame: Serial pharmacokinetic blood samples for theophylline collected on Days 1 and 12 before dosing and for 48 hours post-dose. Serial pharmacokinetic blood samples for quinine collected on Days 11 and 12 before dosing and for 8 hours after the morning dose.
Population: A total of 24 healthy adult male subjects participated in this study, 22 of whom completed. Pharmacokinetic analyses of theophylline are based on 19 subjects (data for 2 subjects excluded due to vomiting post-dose and for 1 subject as an outlier. Pharmacokinetic analyses of quinine are based on 20 subjects (excluding the two who vomited).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Theophylline Alone | Maximum Plasma Concentration(Cmax) | 9.58 ug/mL | Standard Deviation 1.66 |
| Quinine Alone | Maximum Plasma Concentration(Cmax) | 6.63 ug/mL | Standard Deviation 1.63 |
| Theophylline in the Presence of Quinine | Maximum Plasma Concentration(Cmax) | 9.81 ug/mL | Standard Deviation 1.35 |
| Quinine in the Presence of Theophylline | Maximum Plasma Concentration(Cmax) | 7.47 ug/mL | Standard Deviation 1.77 |
Secondary
Electrocardiogram (ECG) Evaluation of the Maximum QT Interval Corrected for Heartrate (QTc), Quinine Study Day 11.
The QT interval assesses cardiac repolarization and risk for arrhythmias. It is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. QTc is the QT interval corrected for heartrate.
Time frame: 5 hours - measured 1 hour pre-dose and then at 4 hours after the morning dose on Day 11
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Theophylline Alone | Electrocardiogram (ECG) Evaluation of the Maximum QT Interval Corrected for Heartrate (QTc), Quinine Study Day 11. | 453.33 msec |
| Quinine Alone | Electrocardiogram (ECG) Evaluation of the Maximum QT Interval Corrected for Heartrate (QTc), Quinine Study Day 11. | 451.33 msec |
Secondary
Electrocardiogram (ECG) Evaluation of the Maximum QT Interval Corrected for Heartrate (QTc), Theophylline Co-administered With Quinine, Study Day 12.
The QT interval assesses cardiac repolarization and risk for arrhythmias. It is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. QTc is the QT interval corrected for heartrate.
Time frame: 5 hours - measured 1 hour pre-dose and then at 4 hours post-dose on Day 12
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Theophylline Alone | Electrocardiogram (ECG) Evaluation of the Maximum QT Interval Corrected for Heartrate (QTc), Theophylline Co-administered With Quinine, Study Day 12. | 452 msec |
| Quinine Alone | Electrocardiogram (ECG) Evaluation of the Maximum QT Interval Corrected for Heartrate (QTc), Theophylline Co-administered With Quinine, Study Day 12. | 455.33 msec |