Behm Martin O, Yee Ka Lai, Liu Rachael, Levine Vanessa, Panebianco Deborah, Fackler Paul
Merck & Co., Inc., Kenilworth, NJ, USA.
Millenium: The Takeda Oncology Company, Cambridge, MA, USA.
Clin Drug Investig. 2017 Jun;37(6):571-579. doi: 10.1007/s40261-017-0512-5.
Doravirine is a novel non-nucleoside reverse transcriptase inhibitor being developed for the treatment of HIV-1. In two open-label, single-dose, randomized, two-period, crossover trials, the bioavailability of doravirine administered alone or in a fixed-dose combination (FDC) was determined under fed and fasted conditions.
Doravirine 100 mg alone or with lamivudine and tenofovir disoproxil fumarate (each 300 mg) were administered to healthy subjects fasted or 30 min after a high-fat, high-calorie breakfast. Twenty-eight subjects, aged 26-55 years, enrolled (doravirine, n = 14; FDC, n = 14). The sequence of fed/fasted treatment was randomized (1:1). Pharmacokinetic data were analyzed as geometric mean ratios (GMRs) with 90% confidence intervals.
Doravirine area under the plasma concentration-time curve (AUC) from time zero to infinity (fed/fasted GMRs: alone 1.16 [1.06-1.26]; FDC 1.10 [1.02-1.20]), AUC from time zero to the last measurement (GMRs: alone 1.18 [1.08-1.29]; FDC 1.10 [1.01-1.20]), and plasma concentration 24 h after administration (GMRs: alone 1.36 [1.19-1.55]; FDC 1.26 [1.13-1.41]) values increased in the fed versus fasted state when administered alone or as the FDC; the magnitude was not clinically meaningful. Doravirine maximum achieved concentration was similar after fed or fasted administration for both doravirine alone and FDC (GMRs: alone 1.03 [0.89-1.19]; FDC 0.95 [0.80-1.12]). The pharmacokinetics of tenofovir and lamivudine in the FDC were also slightly altered by administration with food; the changes were not clinically meaningful.
All treatments were generally well tolerated. Food had no clinically meaningful effect on doravirine 100 mg alone or as part of an FDC.
多韦拉韦是一种正在研发用于治疗HIV-1的新型非核苷类逆转录酶抑制剂。在两项开放标签、单剂量、随机、两周期、交叉试验中，测定了单独给药或固定剂量组合（FDC）给药时多韦拉韦在进食和空腹条件下的生物利用度。
将100mg多韦拉韦单独给药或与拉米夫定和替诺福韦酯（各300mg）联合给药，分别给予空腹或高脂高热量早餐后30分钟的健康受试者。招募了28名年龄在26至55岁之间的受试者（多韦拉韦组，n = 14；FDC组，n = 14）。进食/空腹治疗顺序随机分配（1:1）。药代动力学数据以几何平均比值（GMR）及其90%置信区间进行分析。
单独给药或作为FDC给药时，从时间零至无穷大的多韦拉韦血浆浓度-时间曲线下面积（AUC）（进食/空腹GMR：单独给药时为1.16 [1.06 - 1.26]；FDC为1.10 [1.02 - 1.20]）、从时间零至最后一次测量的AUC（GMR：单独给药时为1.18 [1.08 - 1.29]；FDC为1.10 [1.01 - 1.20]）以及给药后24小时的血浆浓度（GMR：单独给药时为1.36 [1.19 - 1.55]；FDC为1.26 [1.13 - 1.41]）值在进食状态下较空腹状态增加；其幅度无临床意义。单独给药的多韦拉韦和FDC在进食或空腹给药后的最大血药浓度相似（GMR：单独给药时为1.03 [0.89 - 1.19]；FDC为0.95 [0.80 - 1.12]）。FDC中替诺福韦和拉米夫定的药代动力学也因与食物同服而略有改变；这些变化无临床意义。
所有治疗总体耐受性良好。食物对单独服用的100mg多韦拉韦或作为FDC一部分的多韦拉韦无临床意义上的影响。
