Merck & Co., Inc., Kenilworth, NJ, USA.
PRA Health Sciences, Raleigh, NC, USA.
Clin Pharmacol Drug Dev. 2020 Feb;9(2):151-161. doi: 10.1002/cpdd.699. Epub 2019 May 23.
Doravirine is a novel nonnucleoside reverse transcriptase inhibitor indicated for the treatment of HIV type 1 infection. A subset of people living with HIV receives methadone for the treatment of opioid addiction. The current study (NCT02715700) was an open-label, multiple-dose, drug interaction study in participants on a methadone maintenance program to investigate potential drug-drug interactions between doravirine and methadone. Participants received a stable methadone maintenance dose of 20 to 180 mg once daily for 14 days prior to day 1 and remained on their maintenance dose over days 1 through 7. On days 2 through 6, an oral dose of doravirine 100 mg was coadministered. For doravirine and methadone pharmacokinetic analysis, blood samples were collected before dosing through 24 hours after dosing. Fourteen participants were enrolled; all participants completed the study. For R-methadone, geometric least squares mean ratios (90% confidence intervals) for dose-normalized area under the plasma concentration-time curve from time zero to 24 hours, plasma concentration at 24 hours, and maximum plasma concentration ([methadone + doravirine]/methadone alone) were 0.95 (0.90-1.01), 0.95 (0.88-1.03), and 0.98 (0.93-1.03), respectively. For doravirine, based on a comparison with historical data, modest decreases in area under the plasma concentration-time curve from time zero to 24 hours, plasma concentration at 24 hours, and maximum plasma concentration were observed after coadministration of doravirine and methadone; geometric least squares mean ratios ([methadone + doravirine]/doravirine alone [90% confidence intervals]) were 0.74 (0.61-0.90), 0.80 (0.63-1.03), and 0.76 (0.63-0.91), respectively. Coadministration of doravirine and methadone was generally well tolerated. No serious adverse events occurred, and there were no discontinuations. In conclusion, coadministration of methadone and doravirine did not have a clinically meaningful effect on the pharmacokinetic profile of either agent.
多伟拉韦是一种新型非核苷类逆转录酶抑制剂，适用于治疗人类免疫缺陷病毒 1 型感染。一小部分艾滋病毒感染者接受美沙酮治疗阿片类药物成瘾。本研究（NCT02715700）是一项纳入美沙酮维持治疗方案参与者的开放性、多剂量、药物相互作用研究，旨在研究多伟拉韦和美沙酮之间潜在的药物相互作用。参与者在第 1 天之前连续 14 天接受稳定的美沙酮维持剂量 20 至 180 毫克，每日 1 次，并且在第 1 天至第 7 天期间继续接受维持剂量。在第 2 天至第 6 天，口服多伟拉韦 100 毫克。对于多伟拉韦和美沙酮的药代动力学分析，在给药前和给药后 24 小时内采集血样。共纳入 14 名参与者，所有参与者均完成了研究。对于 R-美沙酮，剂量标准化的 0 至 24 小时血浆浓度-时间曲线下面积、24 小时血浆浓度和最大血浆浓度的几何均数比值（90%置信区间）[（美沙酮+多伟拉韦）/美沙酮]分别为 0.95（0.90-1.01）、0.95（0.88-1.03）和 0.98（0.93-1.03）。对于多伟拉韦，与历史数据相比，在美沙酮合并用药后观察到多伟拉韦的 0 至 24 小时血浆浓度-时间曲线下面积、24 小时血浆浓度和最大血浆浓度略有降低；剂量标准化的 0 至 24 小时血浆浓度-时间曲线下面积、24 小时血浆浓度和最大血浆浓度的几何均数比值[（美沙酮+多伟拉韦）/多伟拉韦]分别为 0.74（0.61-0.90）、0.80（0.63-1.03）和 0.76（0.63-0.91）。多伟拉韦和美沙酮合用总体上耐受性良好。未发生严重不良事件，也无停药。结论是，美沙酮和多伟拉韦合用对两者的药代动力学特征均无临床意义的影响。
