A Phase 1 interventional study of Theophylline 300mg and Quinine 648 mg in Pharmacokinetics, sponsored by Mutual Pharmaceutical Company, Inc.. Completed at 1 site in United States. Open to male participants aged 18 Years to 45 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2009-10-28.
Sponsored by Mutual Pharmaceutical Company, Inc. · Phase 1, Interventional, and Basic science
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.
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.
Mutual Pharmaceutical Company, Inc. is the lead sponsor of 42 studies on the registry; none are open to participants now.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
baseline theophylline pharmacokinetics
Drug: Theophylline 300mg
baseline quinine pharmacokinetics at steady state
Drug: Quinine 648 mg
Theophylline pharmacokinetics in the presence of steady state quinine and quinine pharmacokinetics in the presence of theophylline.
Drug: Theophylline 300 mg · Drug: Quinine 648 mg
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.
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.
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.
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.
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.
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.
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
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
Twenty-four (24) healthy, non-smoking, adult male volunteers from the community at large were enrolled.
| Milestone | Theophylline Alone, Quinine Alone, Theophylline With Quinine |
|---|---|
| Started | 24 |
| Completed | 24 |
| Not completed | 0 |
| Milestone | Theophylline Alone, Quinine Alone, Theophylline With Quinine |
|---|---|
| Started | 24 |
| Completed | 24 |
| Not completed | 0 |
| Milestone | Theophylline Alone, Quinine Alone, Theophylline With Quinine |
|---|---|
| Started | 24 |
| Completed | 22 |
| Not completed | 2 |
| Withdrew: Adverse event | 2 |
| Milestone | Theophylline Alone, Quinine Alone, Theophylline With Quinine |
|---|---|
| Started | 22 |
| Completed | 22 |
| Not completed | 0 |
The maximum or peak concentration that the drug reaches in the plasma.
| ug/mL | Theophylline Alone | Quinine Alone | Theophylline in the Presence of Quinine | Quinine in the Presence of Theophylline |
|---|---|---|---|---|
| Maximum Plasma Concentration(Cmax) | 9.58 ± 1.66 | 6.63 ± 1.63 | 9.81 ± 1.35 | 7.47 ± 1.77 |
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.
| ug-hr/mL | Theophylline Alone | Quinine Alone | Theophylline in Presence of Quinine | Quinine in Presence of Theophylline |
|---|---|---|---|---|
| Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 103.47 ± 35.82 | 45.17 ± 11.41 | 92.72 ± 31.17 | 51.68 ± 13.11 |
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.
| ug-hr/mL | Theophylline Alone | Theophylline in Presence of Quinine |
|---|---|---|
| Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]. | 108.21 ± 37.33 | 96.88 ± 31.95 |
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.
| msec | 1 Hour Before Morning Dose of Quinine on Study Day 11 | 4 Hours After Morning Dose of Quinine on Study Day 11 |
|---|---|---|
| Electrocardiogram (ECG) Evaluation of the Maximum QT Interval Corrected for Heartrate (QTc), Quinine Study Day 11. | 453.33 | 451.33 |
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.
| msec | 1 Hour Before Co-Administered Dose of Theophylline/Quinine | 4 Hours After Co-Administered Dose of Theophylline/Quinine |
|---|---|---|
| Electrocardiogram (ECG) Evaluation of the Maximum QT Interval Corrected for Heartrate (QTc), Theophylline Co-administered With Quinine, Study Day 12. | 452 | 455.33 |
Non-serious events are listed at a 4.2% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Theophylline Alone | — | — | — |
| Quinine Alone | — | — | — |
| Theophylline Co-administered With Quinine | — | — | — |
| Event | Theophylline Alone | Quinine Alone | Theophylline Co-administered With Quinine |
|---|---|---|---|
| drug hypersensitivityGeneral disorders | 0/24 | 1/24 | 0/24 |
| Event | Theophylline Alone | Quinine Alone | Theophylline Co-administered With Quinine |
|---|---|---|---|
| tinnitusEar and labyrinth disorders | 0/24 | 13/24 | 0/24 |
| nauseaGastrointestinal disorders | 1/24 | 5/24 | 12/24 |
| dizzinessNervous system disorders | 2/24 | 6/24 | 9/24 |
| headacheNervous system disorders | 1/24 | 2/24 | 9/24 |
| ear discomfortEar and labyrinth disorders | 0/24 | 7/24 | 0/24 |
| hypoacusisEar and labyrinth disorders | 0/24 | 3/24 | 0/24 |
| pallorGeneral disorders | 0/24 | 1/24 | 3/24 |
| dysgeusiaNervous system disorders | 0/24 | 3/24 | 0/24 |
| syncopeNervous system disorders | 1/24 | 0/24 | 3/24 |
| deafnessEar and labyrinth disorders | 0/24 | 2/24 | 1/24 |
| Age, Categorical(Participants) | Theophylline Alone, Quinine Alone, Theophylline With Quinine |
|---|---|
| <=18 years | 1 |
| Between 18 and 65 years | 23 |
| >=65 years | 0 |
| Age Continuous(years) | Theophylline Alone, Quinine Alone, Theophylline With Quinine |
|---|---|
| Mean | 27.25 ± 6.038 |
| Sex: Female, Male(Participants) | Theophylline Alone, Quinine Alone, Theophylline With Quinine |
|---|---|
| Female | 0 |
| Male | 24 |
| Ethnicity (NIH/OMB)(Participants) | Theophylline Alone, Quinine Alone, Theophylline With Quinine |
|---|---|
| Hispanic or Latino | 0 |
| Not Hispanic or Latino | 24 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | Theophylline Alone, Quinine Alone, Theophylline With Quinine |
|---|---|
| United States | 24 |
This study is completed, as verified in Oct 2009. You cannot join it, but the record below documents what was studied.
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Mutual Pharmaceutical Company, Inc.