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首页> 外文期刊>Drug Design, Development and Therapy >Darunavir–cobicistat–emtricitabine–tenofovir alafenamide: safety and efficacy of a protease inhibitor in the modern era
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Darunavir–cobicistat–emtricitabine–tenofovir alafenamide: safety and efficacy of a protease inhibitor in the modern era

机译：Darunavir–cobicistat–emtricitabine–tenofovir alafenamide：现代蛋白酶抑制剂的安全性和有效性

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摘要

A fixed-dose combination consisting of darunavir (Drv), cobicistat (Cobi), emtricitabine (2',3'-dideoxy-5-fluoro-3'-thiacytidine [FTC]), and tenofovir alafenamide (Taf) has been recently approved by the European Medicines Agency for the treatment of HIV infection, and is the first ever protease-inhibitor-based single-tablet regimen. This article provides a detailed description of its pharmacokinetic, efficacy, and safety profile. The pharmacokinetics of single compounds were analyzed, with a special focus on contrasts between Drv/Cobi and Drv/ritonavir (Rtv). When comparing Cobi and Rtv, multiple interactions must be taken into account: in comparison to Rtv, Cobi is a more selective CYP3A4 inhibitor and has no clinical effect on other isoenzymes inhibited by Rtv (eg, 2C8 and 2C9). Moreover, unlike Cobi, Rtv shows in vivo induction activity on some CYP isoenzymes (eg, 1A2, 2C19, 2C8, 2C9, and 2B6), glucuronyltransferases (eg, UGT1A4), and Pgp. Drv-Cobi-FTC-Taf has recently been demonstrated to be of equal efficacy to Drv-Rtv and other protease inhibitors in both experienced (EMERALD study) and na?ve (AMBER study) patients. Moreover, kidney and bone safety profiles have been shown to be good, as has central nervous system tolerance. Total cholesterol:low-density-lipoprotein cholesterol and total cholesterol:high-density-lipoprotein cholesterol ratios are generally high in Drv-Cobi-FTC-Taf vs Rtv-Drv-FTC + tenofovir disoproxil fumarate. An unlikely role of Drv in influencing cardiovascular risk in HIV infection has also been reported. Kidney safety profile is influenced by Cobi, with an increase in creatinine plasma concentration of 0.05–0.1 mg/dL and a parallel glomerular filtration-rate reduction of 10 mL/min within the first 4 weeks after Cobi introduction, which remains stable during treatment. Bone and central nervous system safety profiles were found to be good in randomized clinical trials of both experienced and na?ve patients. The efficacy and safety of Drv/Cobi/FTC/Taf are comparable to other drug regimens recommended for HIV treatment.
机译：最近批准了由达那那韦（Drv），考比司他（Cobi），恩曲他滨（2'，3'-dideoxy-5-fluoro-3'-thacytidine [FTC]）和替诺福韦阿拉芬酰胺（Taf）组成的固定剂量组合由欧洲药物管理局（European Medicines Agency）负责治疗HIV感染，并且是有史以来第一个基于蛋白酶抑制剂的单片疗法。本文详细介绍了其药代动力学，功效和安全性。分析了单个化合物的药代动力学，特别侧重于Drv / Cobi与Drv / ritonavir（Rtv）之间的对比。比较Cobi和Rtv时，必须考虑多种相互作用：与Rtv相比，Cobi是一种更具选择性的CYP3A4抑制剂，对其他受Rtv抑制的同功酶（例如2C8和2C9）没有临床作用。此外，与Cobi不同，Rtv对某些CYP同功酶（例如1A2、2C19、2C8、2C9和2B6），葡萄糖醛酸转移酶（例如UGT1A4）和Pgp表现出体内诱导活性。最近，在经验丰富的患者（EMERALD研究）和幼稚的患者（AMBER研究）中，Drv-Cobi-FTC-Taf与Drv-Rtv和其他蛋白酶抑制剂的疗效相同。此外，肾脏和骨骼的安全性已被证明是良好的，中枢神经系统耐受性也很好。总胆固醇：低密度脂蛋白胆固醇和总胆固醇：高密度脂蛋白胆固醇的比率通常在Drv-Cobi-FTC-Taf与Rtv-Drv-FTC +替诺福韦二富马酸富马酸酯中较高。还已经报道了Drv在影响HIV感染中的心血管风险中起不太可能的作用。肾脏的安全性受到Cobi的影响，在Cobi引入后的最初4周内，肌酐血浆浓度增加了0.05–0.1 mg / dL，平行肾小球滤过率降低了10 mL / min，在治疗期间保持稳定。在经验丰富和天真的患者的随机临床试验中，发现骨骼和中枢神经系统的安全性良好。 Drv / Cobi / FTC / Taf的疗效和安全性可与推荐用于HIV治疗的其他药物方案相媲美。

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