The Influence of Cobicistat or Ritonavir on Dabigatran Pharmacokinetics and Phar

抗逆转录病毒(ARV)药物治疗的进展已经转化为艾滋病毒携带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人群中所占的比例越来越大。此外，艾滋病毒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疾病。考虑到许多老年、甚至非老年艾滋病毒患者将需要短期或长期抗凝来预防和/或治疗系统性血栓，抗逆转录病毒药物与抗凝药物之间的潜在相互作用尤其令人担忧。达比卡特兰是一种口服不可逆的竞争性直接凝血酶抑制剂，在预防房颤患者和骨科手术患者的血栓栓塞症方面分别优于华法林和依诺肝素，而不低于依诺肝素。 虽然达比加兰本身不是通透性糖蛋白(P-gp)的底物，但其失活的前体药物达比加兰etexilate是P-gp的底物。联合应用达比卡特兰和P-gp调节剂已导致达比卡特兰暴露的显著变化。药代动力学增强剂利托那韦和考比西坦作为P-gp的抑制剂，有望增加达比卡特兰的血浆浓度；然而，到目前为止，这两种药物都没有与达比卡特兰etexilate联合进行研究。因此，这项研究的目的是确定利托那韦或可比司坦单用与达比卡特兰依西酯单独联合给药是否会增加健康志愿者体内达比加兰的全身暴露，如果是的话，调整这些药物的给药时间是否可以绕过这种相互作用。 在这项开放标签研究中，32名健康志愿者被分配到两组中的一组。A组16例，服用利托那韦22天；B组16例，服用钴钠22天。所有受试者分别接受3次单剂量达比卡特兰依昔洛特治疗。Dabigatran的药代动力学(PK)和药效学(PD)采样将在第01天、第191天20天和第261天27天进行。用蜕皮素凝血时间(ECT)测定达比加兰的局部放电效应。 用WinNonlin专业计算机程序(5.2版；Pharsight Corporation，Mountain View，CA)使用非隔室方法测定Dabigatran PK/PD参数。比较两组间的PK/PD参数：0~24小时曲线下面积(AUC0~24)、最大达比卡特兰血药浓度(Cmax)、0~无限小时曲线下面积(AUC0-)、达峰时间(Tmax)、半衰期(T)、表观清除率(CL/F)、0~24小时效应曲线下面积(AUEC0~24)、最大有效基线比(ERmax)。 这项研究已经完成了研究两个分支的所有科目的全面招生。部分数据在第15届国际艾滋病毒和肝炎临床药理学研讨会上发表， 2014年5月，华盛顿特区，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机会性感染年度会议。在《循环》杂志上发表了一篇简短的研究通讯。全文发表在《抗菌剂与化疗》上。引文包括在年度报告中。

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.