The Influence of Cobicistat or Ritonavir on Dabigatran Pharmacokinetics and Phar

抗逆转录病毒药物治疗的进展已转化为艾滋病毒感染者寿命的延长和生活质量的改善;因此，老年人在当今艾滋病毒感染者中所占比例越来越大。此外，HIV感染本身已被认为是一种以高凝状态和过早免疫老化为特征的病症。考虑到许多老年甚至非老年HIV患者需要短期或长期抗凝治疗以预防和/或治疗全身性栓塞，抗逆转录病毒药物和抗凝药物之间的潜在相互作用尤其值得关注。达比加群（达比加群酯）是一种口服不可逆、竞争性直接凝血酶抑制剂，在预防房颤患者血栓栓塞和骨科手术患者血栓栓塞方面分别优于华法林（上级）和非劣效于依诺肝素。 虽然达比加群本身不是渗透性糖蛋白（P-gp）的底物，但其非活性前药达比加群酯是P-gp的底物。达比加群酯与P-gp调节剂联合给药导致达比加群暴露量发生显著变化。药代动力学增强剂利托那韦和cobicistat作为P-gp抑制剂，预期会增加达比加群的血药浓度;然而，迄今为止，尚未研究过这两种药物与达比加群酯的联合用药。因此，本研究的目的是确定利托那韦或cobicistat与达比加群酯单独联合给药是否会增加健康志愿者中达比加群的全身暴露量，如果是，调整这些药物的给药时间是否可以避免这种相互作用。 在这项开放标签研究中，32名健康志愿者被分配到2组之一。A组由16例将接受22天利托那韦治疗的受试者组成; B组由16例将接受22天可比司他治疗的受试者组成。所有受试者均接受了3次达比加群酯单次给药。达比加群的药代动力学（PK）和药效学（PD）采样将在第0 - 1天、第191 - 20天和第261 - 27天进行。达比加群的PD效应通过ecarin凝血时间（ECT）测量进行表征。 使用WinNonlin专业计算机程序（版本5.2; Pharsight Corporation，山景，CA），采用非房室方法测定达比加群PK/PD参数。将比较组间的以下PK/PD参数：0 - 24小时曲线下面积（AUC 0 -24）、达比加群总血药峰浓度（Cmax）、0-无穷大时间曲线下面积（AUC 0-）、至血药峰浓度时间（tmax）、终末半衰期（T）、表观口服清除率（CL/F），0 - 24小时效应曲线下面积（AUC 0 -24）和相对于基线的最大效应比（ER max）。 本研究的两个组均完成了所有受试者的完全入组。 部分数据在第15届HIV和肝炎临床药理学国际研讨会上发表， 华盛顿，2014年5月，以及2015年和2016年在马萨诸塞州波士顿（2015年）和华盛顿州西雅图（2016年）举行的逆转录病毒和病毒感染年会。 在《循环》杂志上发表了一份简短的研究信函。 全文发表在《抗菌药物与化疗》上。引文列入年度报告。

Advances in antiretroviral (ARV) pharmacotherapy have translated to increased longevity and improved quality of life in people living with HIV; hence, elderly individuals comprise an increasing proportion of todays HIV population. Moreover, HIV infection itself has become recognized as a condition characterized by a hypercoaguable state and premature immunologic aging. Potential interactions between ARVs and anticoagulant medications are of particular concern considering that many elderly, and even non-elderly HIV patients will require short-term or chronic anticoagulation to prevent and/or treat systemic embolism. Dabigatran, administered as dabigatran etexilate, is an oral irreversible, competitive direct thrombin inhibitor, which has been shown to be superior to warfarin, and non-inferior to enoxaparin, in preventing thromboembolism in patients with atrial fibrillation and undergoing orthopedic surgery, respectively. While dabigatran itself is not a substrate of Permeability-glycoprotein (P-gp), its inactive pro-drug, dabigatran etexilate, is a substrate of P-gp. Co-administration of dabigatran etexilate with P-gp modulators has resulted in significant changes in dabigatran exposure. The pharmacokinetic enhancers, ritonavir and cobicistat, as inhibitors of P-gp, are expected to increase plasma concentrations of dabigatran; however, neither agent has been studied in combination with dabigatran etexilate, to date. Hence, the purpose of this study is to determine whether the separate co-administration of ritonavir or cobicistat with dabigatran etexilate increases the systemic exposure of dabigatran in healthy volunteers, and if so, whether adjusting the administration times of these medications can circumvent this interaction. In this open-label study, 32 healthy volunteers were assigned to 1 of 2 groups. Group A consisted of 16 subjects who will take 22 days of ritonavir; Group B consisted of 16 subjects who will take 22 days of cobicistat. All subjects received 3 separated single doses of dabigatran etexilate. Pharmacokinetic (PK) and pharmacodynamics (PD) sampling for dabigatran will occur on Days 0 1, Day 191 20, and Day 261 27. The PD effects of dabigatran were characterized via ecarin clotting time (ECT) measurements. Dabigatran PK/PD parameters were determined using non-compartmental methods with the WinNonlin professional computer program (version 5.2; Pharsight Corporation, Mountain View, CA). The following PK/PD parameters will be compared between the groups: area under the curve from 0 to 24 hours (AUC0-24), maximum total dabigatran plasma concentration (Cmax), area under the curve from 0 to infinity hours (AUC0-), time to maximum plasma concentration (tmax), terminal half-life (T), apparent oral clearance (CL/F), area under the effect curve from 0 to 24 hours (AUEC0-24), and the maximum effect ratio over baseline (ERmax). This study has completed full enrollment of all subjects in both arms of the study. Partial data was presented at 15th International Workshop on Clinical Pharmacology in HIV and Hepatitis, Washington DC, May, 2014 and the 2015 and 2016 Annual Conference on Retroviruses and Opportunistic Infections in Boston, MA (2015) and Seattle, WA (2016. A brief research letter publication was published in the journal "Circulation". A full manuscript is published in "Antimicrobial Agents and Chemotherapy". Citation is included in the annual report.