Kakuda Thomas N, Van De Casteele Tom, Petrovic Romana, Neujens Mark, Salih Hiba, Opsomer Magda, Hoetelmans Richard Mw
Janssen Research & Development, LLC, Titusville, NJ, USA.
Antivir Ther. 2014;19(6):597-606. doi: 10.3851/IMP2814. Epub 2014 Jun 25.
Darunavir requires pharmacokinetic enhancement to increase its bioavailability. Cobicistat is potentially an alternative pharmacokinetic booster to ritonavir. Bioequivalence of a darunavir/cobicistat fixed-dose combination (FDC) versus darunavir and cobicistat co-administered as single agents and the effect of a high-fat meal on the pharmacokinetics of the FDC were evaluated.
In this Phase I, open-label, randomized, three-panel, crossover study (NCT01619527), healthy volunteers received a single dose of darunavir (800 mg) with cobicistat (150 mg) as either an FDC or as single agents co-administered under fasted (panel 1, n=74) or fed (breakfast, panel 2, n=40) conditions, or as the FDC under fasted versus fed (high-fat breakfast) conditions (panel 3, n=19), with a ≥7 day washout period between treatments. Pharmacokinetic profiles, safety and tolerability were assessed.
90% confidence intervals of the least square mean ratios for darunavir and cobicistat maximum plasma concentration and area under the plasma concentration-time curve (AUC) were all within 80.00% and 125.00% in panels 1 and 2. Administration of the FDC with a high-fat breakfast significantly increased darunavir maximum plasma concentration 2.27-fold and AUC 1.63-1.70-fold, whereas cobicistat pharmacokinetics were unaffected. No volunteers discontinued due to adverse events (AEs). All AEs were grade 1 or 2. Overall, 27 (20%) and 26 (20%) volunteers had ≥1 AE at least possibly related to darunavir and cobicistat, respectively.
Bioequivalence of the darunavir/cobicistat 800/150-mg FDC was demonstrated versus darunavir and cobicistat co-administered as single agents under fasted or fed conditions. Food increased darunavir exposure, therefore, darunavir/cobicistat should be administered with food.
达芦那韦需要进行药代动力学增强以提高其生物利用度。考比司他可能是利托那韦的替代药代动力学增强剂。对达芦那韦/考比司他固定剂量复方制剂（FDC）与达芦那韦和考比司他单药联合给药的生物等效性以及高脂餐对该FDC药代动力学的影响进行了评估。
在这项I期、开放标签、随机、三阶段、交叉研究（NCT01619527）中，健康志愿者接受单剂量达芦那韦（800mg）与考比司他（150mg），给药方式为FDC或在禁食（第1阶段，n = 74）或进食（早餐，第2阶段，n = 40）条件下单药联合给药，或在禁食与进食（高脂早餐）条件下给予FDC（第3阶段，n = 19），治疗之间有≥7天的洗脱期。评估药代动力学特征、安全性和耐受性。
在第1和第2阶段，达芦那韦和考比司他的最大血浆浓度及血浆浓度 - 时间曲线下面积（AUC）的最小二乘均值比的90%置信区间均在80.00%至125.00%范围内。高脂早餐时给予FDC显著提高了达芦那韦的最大血浆浓度2.27倍和AUC 1.63 - 1.70倍，而考比司他的药代动力学未受影响。没有志愿者因不良事件（AE）而停药。所有AE均为1级或2级。总体而言，分别有27名（20%）和26名（20%）志愿者至少有1次AE可能与达芦那韦和考比司他有关。
证明了达芦那韦/考比司他800/150mg FDC与达芦那韦和考比司他在禁食或进食条件下单药联合给药具有生物等效性。食物增加了达芦那韦的暴露量，因此，达芦那韦/考比司他应与食物一起服用。
