Gilead Sciences, Foster City, California.
Clin Infect Dis. 2018 Aug 31;67(6):934-940. doi: 10.1093/cid/ciy201.
Combining antiviral regimens in the hepatitis C virus (HCV)/human immunodeficiency virus (HIV)-coinfected population can be complex as they share overlapping mechanisms for elimination that may result in drug interactions. The pharmacokinetics, safety, and tolerability of sofosbuvir/velpatasvir (SOF/VEL) with multiple antiretroviral (ARV) regimens were evaluated.
Healthy volunteers were enrolled into 2 phase 1, open-label, randomized, multiple-dose, cross-over studies. SOF/VEL and ARV regimens were administered alone and in combination; ARVs (and pharmacokinetic enhancers) included atazanavir (ATV), cobicistat (COBI), darunavir (DRV), dolutegravir (DTG), efavirenz (EFV), elvitegravir (EVG), emtricitabine (FTC), lopinavir (LPV), raltegravir (RAL), rilpivirine (RPV), ritonavir (RTV), tenofovir alafenamide (TAF), and tenofovir disoproxil fumarate (TDF). Geometric least squares means ratios (coadministration:alone) and 90% confidence intervals were constructed for area under the plasma concentration-time curve over the dosing interval, maximum concentration, and trough, for all analytes. Safety and tolerability were also evaluated.
In total, 237 participants were enrolled. No clinically relevant differences in the pharmacokinetics (PK) of SOF, SOF metabolite GS-331007, or VEL were observed other than an approximate 50% decrease in VEL exposure when administered with EFV/FTC/TDF. No clinically relevant differences in the PK of ARVs were observed when administered with SOF/VEL. Study treatments were well tolerated, including no observed creatinine clearance changes during evaluation of TDF-containing regimens.
SOF/VEL and ARV regimens including ATV, COBI, DRV, DTG, EVG, FTC, LPV, RAL, RPV, RTV, TAF, or TDF may be coadministered without dose adjustment. Use of SOF/VEL with EFV-containing regimens is not recommended due to an approximate 50% reduction in VEL exposure.
在丙型肝炎病毒（HCV）/人类免疫缺陷病毒（HIV）合并感染人群中联合使用抗病毒药物可能较为复杂，因为这些药物的消除机制存在重叠，可能导致药物相互作用。本文评估了索磷布韦/维帕他韦（SOF/VEL）与多种抗逆转录病毒（ARV）方案联合应用的药代动力学、安全性和耐受性。
健康志愿者参加了 2 项 1 期、开放性、随机、多剂量、交叉研究。SOF/VEL 与 ARV 方案单独或联合应用；ARV（和药代动力学增强剂）包括阿扎那韦（ATV）、考比司他（COBI）、达芦那韦（DRV）、多替拉韦（DTG）、依非韦伦（EFV）、艾维雷韦（EVG）、恩曲他滨（FTC）、洛匹那韦（LPV）、拉替拉韦（RAL）、利匹韦林（RPV）、利托那韦（RTV）、替诺福韦艾拉酚胺（TAF）和替诺福韦二吡呋酯（TDF）。构建了所有分析物的药时曲线下面积（AUC）、最大浓度和谷浓度的几何均数比值（合用：单用）和 90%置信区间。还评估了安全性和耐受性。
共纳入 237 名参与者。与 SOF、SOF 代谢物 GS-331007 或 VEL 相关的药代动力学（PK）无临床相关差异，除了与 EFV/FTC/TDF 联合应用时 VEL 暴露量降低约 50%。与 SOF/VEL 联合应用时，ARV 的 PK 无临床相关差异。研究治疗药物耐受性良好，包括在评估含 TDF 方案期间未观察到肌酐清除率的变化。
SOF/VEL 与包含 ATV、COBI、DRV、DTG、EVG、FTC、LPV、RAL、RPV、RTV、TAF 或 TDF 的 ARV 方案可联合应用，无需调整剂量。由于 VEL 暴露量降低约 50%，不建议 SOF/VEL 与 EFV 联合应用。
