Janssen Research and Development, Turnhoutseweg 30, B-2340, Beerse, Belgium.
Model Answers R&D, Brisbane, Australia.
AAPS J. 2021 Jun 7;23(4):82. doi: 10.1208/s12248-021-00607-8.
The single-tablet regimen darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg has undergone phase III studies AMBER (NCT02431247) and EMERALD (NCT02269917) in HIV-infected patients. An existing population pharmacokinetic (PopPK) model for cobicistat-boosted darunavir (DRV) was updated to describe DRV PK in AMBER and EMERALD. For TAF, a PopPK model was developed using richly sampled phase I/II data and updated with sparsely sampled AMBER data. Individual exposure metrics for DRV and TAF in patients receiving D/C/F/TAF were derived (AMBER, n=356; EMERALD, n=750). The DRV PopPK model is a two-compartment model with sequential zero-order, first-order input. TAF PK is described by a one-compartment model with dual parallel input for absorption (slow and fast pathway). DRV covariates were α1-acid-glycoprotein and body weight. TAF covariates were lean body weight and α1-acid-glycoprotein. DRV and TAF PK were unaffected by age, race, or gender. Estimated DRV mean (SD) C and AUC, respectively, were 1899 (759) ng/mL and 87,909 (20,232) ngh/mL in AMBER; 1813 (859) ng/mL and 85,972 (22,413) ngh/mL in EMERALD. Estimated TAF mean (SD) AUC was 132 (41) ng*h/mL. These PK parameters were in line with historical data. No apparent relationships of DRV or TAF exposure with efficacy (virologic response) or safety (metabolic, cardiac, liver, gastrointestinal, skin, bone, renal, pancreas, lipid events) parameters were seen. Additionally, our findings demonstrate that in patients with low plasma concentrations, there is no risk of decreased virologic response or virologic rebound. This supports the use of a once-daily, single-tablet regimen of D/C/F/TAF 800/150/200/10 mg for the treatment of HIV-1-infected subjects.
达拉韦林/考比司他/恩曲他滨/替诺福韦艾拉酚胺（D/C/F/TAF）800/150/200/10 毫克单片治疗方案已经在感染 HIV 的患者中完成了 AMBER（NCT02431247）和 EMERALD（NCT02269917）的 III 期研究。现有的考比司他增强型达拉韦林（DRV）群体药代动力学（PopPK）模型经过更新，可用于描述 AMBER 和 EMERALD 中的 DRV 药代动力学。对于 TAF，使用丰富采样的 I/II 期数据开发了一个 PopPK 模型，并使用稀疏采样的 AMBER 数据进行了更新。从接受 D/C/F/TAF 治疗的患者中得出了 DRV 和 TAF 的个体暴露指标（AMBER，n=356；EMERALD，n=750）。DRV PopPK 模型是一个具有顺序零级、一级输入的两室模型。TAF PK 由一个具有双平行吸收途径（慢途径和快途径）的一室模型描述。DRV 的协变量是α1-酸性糖蛋白和体重。TAF 的协变量是瘦体重和α1-酸性糖蛋白。年龄、种族或性别对 DRV 和 TAF 的药代动力学没有影响。在 AMBER 中，估计的 DRV 平均（SD）C 和 AUC 分别为 1899（759）ng/mL 和 87909（20232）ngh/mL；在 EMERALD 中，分别为 1813（859）ng/mL 和 85972（22413）ngh/mL。估计的 TAF 平均（SD）AUC 为 132（41）ng*h/mL。这些 PK 参数与历史数据一致。未观察到 DRV 或 TAF 暴露与疗效（病毒学反应）或安全性（代谢、心脏、肝脏、胃肠道、皮肤、骨骼、肾脏、胰腺、脂质事件）参数之间存在明显关系。此外，我们的研究结果表明，在血浆浓度较低的患者中，不会降低病毒学反应或出现病毒学反弹的风险。这支持使用达拉韦林/考比司他/恩曲他滨/替诺福韦艾拉酚胺 800/150/200/10 毫克的每日一次、单片治疗方案治疗 HIV-1 感染患者。
