DeJesus Edwin, Saleh Soundos, Cheng Sue, van der Mey Dorina, Becker Corina, Frey Reiner, Unger Sigrun, Mueck Wolfgang
1 Orlando Immunology Center, Orlando, FL, USA.
2 Clinical Pharmacology, Bayer AG, Wuppertal, Germany.
Pulm Circ. 2019 Apr-Jun;9(2):2045894019848644. doi: 10.1177/2045894019848644.
Riociguat, a first-in-class soluble guanylate cyclase stimulator, is approved for the treatment of pulmonary arterial hypertension (PAH), a serious potential complication of human immunodeficiency virus (HIV) infection. This open-label study investigated the pharmacokinetic drug-drug interaction potential of antiretroviral therapies on riociguat exposure in HIV-infected adults. HIV-infected adults without PAH on stable antiretroviral regimens (efavirenz/emtricitabine/tenofovir disoproxil, emtricitabine/rilpivirine/tenofovir disoproxil, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil, abacavir/dolutegravir/lamivudine, or a ritonavir-boosted triple regimen) for ≥ 6 weeks received a single riociguat dose (0.5 mg). Riociguat pharmacokinetics and safety were assessed; pharmacokinetics was compared with historical healthy volunteer data. Of 41 participants treated (n = 8 in each arm, except n = 9 in the ritonavir-boosted triple regimen arm), 40 were included in the pharmacokinetic analyses. Riociguat median t was 1.00-1.27 h, with comparable maximum concentration (C) across the five background antiretroviral groups. Riociguat exposure was highest with abacavir/dolutegravir/lamivudine, followed by elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil > emtricitabine/rilpivirine/tenofovir disoproxil > ritonavir-boosted triple regimen > efavirenz/emtricitabine/tenofovir disoproxil; riociguat area under the plasma concentration versus time curve (AUC) was approximately threefold higher with abacavir/dolutegravir/lamivudine than efavirenz/emtricitabine/tenofovir disoproxil. Compared with historical data, riociguat exposure in HIV-infected adults was similar when co-administered with efavirenz/emtricitabine/tenofovir disoproxil, slightly increased when administered with ritonavir-boosted triple regimen and increased by approximately threefold when administered with abacavir/dolutegravir/lamivudine. Riociguat was well tolerated, with no new safety findings. Riociguat was well tolerated in adults with HIV on stable background antiretroviral therapy although an apparent increase in AUC of riociguat was observed in patients receiving abacavir/dolutegravir/lamivudine. Patients should be monitored closely during riociguat initiation and dose adjustment for signs and symptoms of hypotension.
利奥西呱是首个获批的可溶性鸟苷酸环化酶刺激剂，被批准用于治疗肺动脉高压（PAH），这是人类免疫缺陷病毒（HIV）感染的一种严重潜在并发症。这项开放标签研究调查了抗逆转录病毒疗法对HIV感染成人中利奥西呱暴露量的药代动力学药物相互作用潜力。接受稳定抗逆转录病毒治疗方案（依非韦伦/恩曲他滨/替诺福韦酯、恩曲他滨/利匹韦林/替诺福韦酯、埃替拉韦/考比司他/恩曲他滨/替诺福韦酯、阿巴卡韦/多替拉韦/拉米夫定或利托那韦增强三联疗法）≥6周且无PAH的HIV感染成人接受单剂量利奥西呱（0.5毫克）治疗。评估了利奥西呱的药代动力学和安全性；并将药代动力学与历史健康志愿者数据进行了比较。在41名接受治疗的参与者中（每个治疗组8名，利托那韦增强三联疗法组9名），40名被纳入药代动力学分析。利奥西呱的中位达峰时间为1.00 - 1.27小时，五个背景抗逆转录病毒治疗组的最大浓度（Cmax）相当。阿巴卡韦/多替拉韦/拉米夫定组的利奥西呱暴露量最高，其次是埃替拉韦/考比司他/恩曲他滨/替诺福韦酯＞恩曲他滨/利匹韦林/替诺福韦酯＞利托那韦增强三联疗法＞依非韦伦/恩曲他滨/替诺福韦酯；阿巴卡韦/多替拉韦/拉米夫定组的利奥西呱血浆浓度-时间曲线下面积（AUC）比依非韦伦/恩曲他滨/替诺福韦酯组高约三倍。与历史数据相比，HIV感染成人与依非韦伦/恩曲他滨/替诺福韦酯合用时利奥西呱的暴露量相似，与利托那韦增强三联疗法合用时略有增加，与阿巴卡韦/多替拉韦/拉米夫定合用时增加约三倍。利奥西呱耐受性良好，未发现新的安全问题。在接受稳定背景抗逆转录病毒治疗的HIV感染成人中，利奥西呱耐受性良好，尽管在接受阿巴卡韦/多替拉韦/拉米夫定的患者中观察到利奥西呱的AUC明显增加。在利奥西呱起始治疗和剂量调整期间，应密切监测患者是否有低血压的体征和症状。
