The Influence of Cobicistat or Ritonavir on Dabigatran Pharmacokinetics and Phar

考比司他或利托那韦对达比加群药代动力学和药物的影响

• 批准号: 10019267
• 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/10019267
• 关键词: ABCB1 gene; Aging; Annual Reports; Anti-Retroviral Agents; Anticoagulants; Anticoagulation; Area; Area Under Curve; Atrial Fibrillation; Blood Circulation; Boston; Chronic; Clinical Pharmacology; Coagulation Process; Data; District of Columbia; Dose; Drug Kinetics; Educational workshop; Elderly; Embolism; Enhancers; Enoxaparin; Enrollment; Genotype; Glycoproteins; HIV; HIV Infections; Half-Life; Hepatitis; Hour; Immunologics; Individual; International; Journals; Letters; Longevity; Manuscripts; Methods; Opportunistic Infections; Oral; Orthopedic Surgery procedures; Patients; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Plasma; Population; Prodrugs; Publications; Publishing; Quality of life; Research; Retroviridae Infections; Ritonavir; Role; Sampling; Thrombin; Thromboembolism; Time; Translating; Warfarin; antimicrobial drug; arm; chemotherapy; computer program; healthy volunteer; improved; inhibitor/antagonist; open label; pharmacokinetics and pharmacodynamics; premature; prevent; symposium; temporal measurement

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.

抗逆转录病毒（ARV）药物治疗的进步已转化为艾滋病毒感染者的寿命延长和生活质量改善；因此，老年人在当今艾滋病毒感染者中所占的比例越来越大。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艾滋病毒患者需要短期或长期抗凝治疗来预防和/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。达比加群酯（达比加群酯）是一种口服不可逆、竞争性直接凝血酶抑制剂，已被证明在预防房颤患者和接受骨科手术患者的血栓栓塞方面分别优于华法林和不劣于依诺肝素。 虽然达比加群本身不是渗透性糖蛋白 (P-gp) 的底物，但其无活性的前药达比加群酯是 P-gp 的底物。达比加群酯与 P-gp 调节剂共同给药导致达比加群暴露量发生显着变化。药代动力学增强剂利托那韦和考比司他作为 P-gp 抑制剂，预计会增加达比加群的血浆浓度；然而，迄今为止，这两种药物均未与达比加群酯联合研究。因此，本研究的目的是确定利托那韦或考比司他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，如果是这样，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 组中的一组。 A 组由 16 名受试者组成，他们将服用 22 天的利托那韦； B 组由 16 名受试者组成，他们将服用 22 天的考比司他。所有受试者均接受 3 次单独的单剂量达比加群酯。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) 测量来表征。 达比加群 PK/PD 参数通过 WinNonlin 专业计算机程序（5.2 版；Pharsight Corporation，Mountain View，CA）使用非房室方法测定。组间比较以下 PK/PD 参数：0 至 24 小时曲线下面积 (AUC0-24)、最大总达比加群血浆浓度 (Cmax)、0 至无限小时曲线下面积 (AUC0-)、达到最大血浆浓度的时间 (tmax)、终末半衰期 (T)、表观口服清除率 (CL/F)、0 至 24 小时效应曲线下面积 (AUEC0-24)，以及相对于基线的最大效应比 (ERmax)。 本研究已完成该研究两个组中所有受试者的全部入组。 部分数据已在第 15 届国际艾滋病毒和肝炎临床药理学研讨会上公布， 华盛顿特区，2014 年 5 月，以及在马萨诸塞州波士顿（2015 年）和华盛顿州西雅图（2016 年）举行的 2015 年和 2016 年逆转录病毒和机会性感染年会。一份简短的研究信件发表在《循环》杂志上。完整的手稿发表在《抗菌药物和化疗》上。年度报告中包含引用。