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

稳态考比司他和达芦那韦/考比司他对健康志愿者中口服抗凝剂（利伐沙班、阿哌沙班）药代动力学和药效学的影响 (CLOTRX)

• 批准号: 10253691
• 负责人: Jomy George
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10253691
• 关键词: Activated Partial Thromboplastin Time measurement; Anti-Retroviral Agents; Anticoagulants; Anticoagulation; Area; Area Under Curve; CYP3A4 gene; Clinical; Coagulation Process; Coupled; Cytochrome P450; Data; Disease; Dose; Drug Interactions; Drug Kinetics; Enzymes; Event; Factor Xa; Food-Drug Interactions; Genes; Genetic Polymorphism; Glycoproteins; HIV; HIV Seronegativity; Half-Life; Hemorrhage; Hour; Isoenzymes; Laboratories; Monitor; Oral; Patients; Permeability; Persons; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Population; Prevention; Property; Regimen; Role; Safety; Security; Time; Transportation; Warfarin; absorption; antiretroviral therapy; healthy volunteer; high risk; inhibitor/antagonist; liver metabolism; medication safety; metabolic abnormality assessment; pharmacokinetics and pharmacodynamics; primary endpoint; secondary endpoint

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.

利伐沙班和阿哌沙班是直接口服抗凝剂（DOACs），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，加上一些药物-药物和食物-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凝血监测。由于安全有效的抗逆转录病毒治疗（ART），人类免疫缺陷病毒（HIV）患者的寿命与HIV阴性患者一样长。艾滋病毒感染者发生血栓栓塞事件的风险较高，doac是这一人群抗凝治疗的可行选择。然而，目前缺乏关于cobicistat （COBI）增强抗逆转录病毒（ARV）与利伐沙班和阿哌沙班联合给药的药物相互作用和安全性数据。利伐沙班和阿哌沙班均由细胞色素P450同工酶（CYP） 3A4代谢，其吸收受通透性糖蛋白（P-gp）调节，均被PK促进剂COBI抑制。因此，当利伐沙班和阿哌沙班与COBI联合使用时，血浆浓度可能显著增加。这是临床关注的问题，因为增加抗凝剂暴露可能导致出血，而没有常规临床监测的安全性。本研究的目的是确定COBI和DRV/COBI稳态浓度对单次口服利伐沙班和阿哌沙班的PK和PD的影响。