Impact of steady state Cobicistat and Darunavir/Cobicistat And on the Pharmacokinetics And Pharmacodynamics of Oral Anticoagulants (Rivaroxaban, Apixaban) In Healthy Volunteers (CLOTRX)

利伐沙班和阿皮沙班是直接口服抗凝剂(DOAC)，用于预防和治疗各种血栓栓塞性疾病。可预测的药代动力学(PK)和药效学(PD)特性，再加上一些药物-药物和食品-药物相互作用，将DOAC与传统使用的抗凝剂华法林区分开来，允许固定剂量，而无需常规的凝血监测。由于安全有效的抗逆转录病毒疗法(ART)，人类免疫缺陷病毒(HIV)患者的寿命与HIV阴性患者一样长。艾滋病毒携带者发生血栓栓塞症的风险更高，DOAC是这一人群中抗凝的可行选择。然而，目前缺乏与利伐沙班和阿皮沙班联合给药的抗逆转录病毒(ARV)方案的药物相互作用和安全性数据。利伐沙班和阿皮沙班均由细胞色素P450同工酶3A4代谢，其吸收受通透性糖蛋白(P-gp)的调节，而通透性糖蛋白(P-gp)受PK启动子Cobi的抑制。因此，当联合用药时，利伐沙班和阿普沙班的血药浓度可能会显著增加。这是临床值得关注的问题，因为在没有常规临床监测的情况下，增加抗凝剂暴露可能会导致出血。本研究的目的是确定Cobi和DRV/Cobi的稳态浓度对单次口服利伐沙班和阿皮沙班的PK和Pd的影响。

Rivaroxaban and apixaban are direct oral anticoagulants (DOACs) used for the prevention and treatment of various thromboembolic disorders. Predictable pharmacokinetic (PK) and pharmacodynamic (PD) properties, coupled with a few drug-drug and food-drug interactions, distinguishes DOACs from traditionally used anticoagulant - warfarin, allowing fixed dosing without routine coagulation monitoring. Patients with human immunodeficiency virus (HIV) are living as long as their HIV negative counterparts due to safe and efficacious antiretroviral therapy (ART). Persons with HIV are at higher risk for thromboembolic events and DOACs are a feasible option for anticoagulation in this population. However, there is a lack of drug interaction and safety data currently on the co-administration cobicistat (COBI)-boosted antiretroviral (ARV) regimens with rivaroxaban and apixaban. Rivaroxaban and apixaban are both metabolized by cytochrome P450 isozyme (CYP) 3A4 and their absorption is modulated by permeability-glycoprotein (P-gp), both of which are inhibited by the PK booster COBI. It is therefore possible that plasma concentrations of rivaroxaban and apixaban may be significantly increased when co-administered together with COBI. This is of clinical concern as increased anticoagulant exposure may result in bleeding without the security of routine clinical monitoring. The purpose of this study is to determine the effects of steady state concentrations of COBI and DRV/COBI on the PK and PD of single oral doses of rivaroxaban and apixaban.