Cao Ying-Jun, Smith Patrick F, Wire Mary Beth, Lou Yu, Lancaster Charles T, Causon Roger C, Bigelow George E, Martinez Elizabeth, Fuchs Edward J, Radebaugh Christine, McCabe Sarah, Hendrix Craig W
Division of Clinical Pharmacology, Johns Hopkins University, Baltimore, Maryland 21287-5554, USA.
Pharmacotherapy. 2008 Jul;28(7):863-74. doi: 10.1592/phco.28.7.863.
To compare steady-state pharmacokinetics and pharmacodynamics of methadone enantiomers when coadministered with fosamprenavir 700 mg-ritonavir 100 mg twice/day.
Open-label, single-sequence, two-period crossover, drug-interaction study.
Two university-affiliated research centers.
Twenty-six opioid-dependent, methadone-maintained, healthy adults.
Subjects received their usual daily dose of methadone alone for 4 days (period 1). Subjects then received the same daily dose of methadone plus fosamprenavir 700 mg-ritonavir 100 mg twice/day for 14 days (period 2).
Blood was collected on days 1-4 (period 1) and on days 11-14 (period 2) for plasma R- and S-methadone concentrations; amprenavir concentrations were assessed during period 2. Opioid-effect measures were assessed in each study period. Subjects served as their own controls for comparison of period 1 with period 2. Coadministration of fosamprenavir-ritonavir with methadone reduced plasma total R-methadone area under the plasma concentration-time curve over the dosing interval at steady state (AUC tau-ss) by 18%, maximum concentration at steady state (Cmax-ss) by 21%, and concentration at the end of the dosing interval at steady state (Ctau-ss) by 11%; time to reach Cmax-ss (Tmax) was delayed by 1.75 hours. Coadministration of fosamprenavir-ritonavir with methadone also reduced plasma total S-methadone AUC tau-ss and Cmax-ss by 43% each, Ctau-ss by 41%, and delayed Tmax by 0.85 hours. Fosamprenavir-ritonavir administered with methadone did not alter plasma amprenavir pharmacokinetics compared with historical control data; nor did it alter the unbound R-methadone at 2 and 6 hours after methadone dosing. Pharmacodynamic indexes remained essentially unchanged after adding fosamprenavir-ritonavir to methadone. No subject demonstrated opioid intoxication or withdrawal, or requested methadone dosage modification.
No adjustment in the dosages of either methadone or fosamprenavir 700 mg-ritonavir 100 mg twice/day is required during coadministration, on the basis of the small reduction in total R-methadone exposure, no change in unbound R-methadone, no clinically important opioid effects, and no change in amprenavir exposure.
比较美沙酮对映体与福沙普那韦700毫克-利托那韦100毫克每日两次联用时的稳态药代动力学和药效学。
开放标签、单序列、两期交叉药物相互作用研究。
两个大学附属研究中心。
26名阿片类药物依赖、接受美沙酮维持治疗的健康成年人。
受试者单独服用其常规每日剂量的美沙酮，持续4天（第1期）。然后，受试者接受相同每日剂量的美沙酮加福沙普那韦700毫克-利托那韦100毫克，每日两次，持续14天（第2期）。
在第1 - 4天（第1期）和第11 - 14天（第2期）采集血液，检测血浆中R-和S-美沙酮浓度；在第2期评估安普那韦浓度。在每个研究期评估阿片类药物效应指标。受试者自身作为对照，用于比较第1期和第2期。福沙普那韦-利托那韦与美沙酮联用时，稳态给药间隔期间血浆总R-美沙酮浓度-时间曲线下面积（AUC tau-ss）降低18%，稳态最大浓度（Cmax-ss）降低21%，稳态给药间隔结束时浓度（Ctau-ss）降低11%；达到Cmax-ss的时间（Tmax）延迟1.75小时。福沙普那韦-利托那韦与美沙酮联用时，血浆总S-美沙酮AUC tau-ss和Cmax-ss也分别降低43%，Ctau-ss降低4l%，Tmax延迟0.85小时。与历史对照数据相比，福沙普那韦-利托那韦与美沙酮联用时未改变血浆安普那韦药代动力学；在美沙酮给药后2小时和6小时，也未改变游离R-美沙酮水平。在美沙酮中加入福沙普那韦-利托那韦后，药效学指标基本保持不变。没有受试者出现阿片类药物中毒或戒断反应，也没有人要求调整美沙酮剂量。
基于总R-美沙酮暴露量略有降低、游离R-美沙酮无变化、无临床重要阿片类药物效应以及安普那韦暴露量无变化，美沙酮与福沙普那韦-利托那韦联用时，无需调整美沙酮或福沙普那韦700毫克-利托那韦100毫克每日两次的剂量。
