Drug - Drug Interaction Study Between Quinine Sulfate and Theophylline
Palabras clave
Abstracto
Descripción
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.
fechas
| Verificado por última vez: | 09/30/2009 |
| Primero enviado: | 10/21/2008 |
| Inscripción estimada enviada: | 10/22/2008 |
| Publicado por primera vez: | 10/23/2008 |
| Última actualización enviada: | 10/19/2009 |
| Última actualización publicada: | 10/27/2009 |
| Fecha de los primeros resultados enviados: | 05/26/2009 |
| Fecha de los primeros resultados de CC enviados: | 05/26/2009 |
| Fecha de los primeros resultados publicados: | 07/16/2009 |
| Fecha de inicio real del estudio: | 07/31/2007 |
| Fecha estimada de finalización primaria: | 08/31/2007 |
| Fecha estimada de finalización del estudio: | 08/31/2007 |
Condición o enfermedad
Intervención / tratamiento
Drug: Theophylline alone
Drug: Quinine alone
Drug: Theophylline with steady state quinine
Drug: Theophylline with steady state quinine
Fase
Grupos de brazos
| Brazo | Intervención / tratamiento |
|---|---|
| Active Comparator: Theophylline alone baseline theophylline pharmacokinetics | Drug: Theophylline alone 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. |
| Active Comparator: Quinine alone baseline quinine pharmacokinetics at steady state | Drug: Quinine alone 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. |
| Experimental: Theophylline with steady state quinine Theophylline pharmacokinetics in the presence of steady state quinine and quinine pharmacokinetics in the presence of theophylline. | Drug: Theophylline with steady state quinine 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. |
Criterio de elegibilidad
| Edades elegibles para estudiar | 18 Years A 18 Years |
| Sexos elegibles para estudiar | Male |
| Acepta voluntarios saludables | si |
| Criterios | 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. |
Salir
Medidas de resultado primarias
1. 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.]
2. 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.]
3. 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.]
Medidas de resultado secundarias
1. 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]
2. 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]
