Bristol-Myers Squibb, P.O. Box 4000, Princeton, NJ, 08540, USA.
Arbutus Biopharma, 701 Veterans Circle, Warminster, PA, 18974, USA.
Clin Pharmacokinet. 2018 Aug;57(8):911-928. doi: 10.1007/s40262-017-0624-3.
Daclatasvir is a first-in-class, highly selective, hepatitis C virus, non-structural protein 5a polymerase replication complex inhibitor with picomolar potency and broad genotypic coverage in vitro. Daclatasvir undergoes rapid absorption, with a time to reach maximum plasma concentration of 1-2 h and an elimination half-life of ~ 10 to 14 h observed in single-ascending dose studies. Steady state was achieved by day 4 in multiple-ascending dose studies. Daclatasvir can be administered without regard to food or pH modifiers. Daclatasvir exposure is similar between healthy subjects and subjects infected with hepatitis C virus. Intrinsic factors such as age, race, or sex do not impact daclatasvir exposure. No dose adjustment is necessary for patients with any degree of hepatic or renal impairment. Daclatasvir has low-to-moderate clearance with the predominant route of elimination via cytochrome P450 3A4-mediated metabolism and P-glycoprotein excretion and intestinal secretion. Renal clearance is a minor route of elimination for daclatasvir. As a result, the dose of daclatasvir should be reduced from 60 to 30 mg once daily when co-administered with strong inhibitors of cytochrome P450 3A4. No dose adjustment is required when daclatasvir is co-administered with moderate inhibitors of cytochrome P450 3A4. The dose of daclatasvir should be increased from 60 to 90 mg once daily when co-administered with moderate inducers of cytochrome P450 3A4. Co-administration of daclatasvir with strong inducers of cytochrome P450 3A4 is contraindicated. Concurrent medications with inhibitory effects on P-glycoprotein without concurrent inhibition of cytochrome P450 3A4 are unlikely to cause marked changes in daclatasvir exposure, as the clearance of daclatasvir is through both cytochrome P450 3A4 and P-glycoprotein. The potential for daclatasvir to affect the pharmacokinetics of concomitantly administered drugs that are substrates of the cytochrome P450 enzyme system is low. In vitro, daclatasvir is a weak-to-moderate inhibitor of transporters including organic cation transporter 1, P-glycoprotein, organic transporting polypeptide 1B1, organic transporting polypeptide 1B3, and breast cancer resistance protein, although in clinical studies, daclatasvir has not altered the pharmacokinetics of concomitantly administered drugs that are substrates of these transporters to an appreciable degree, except for rosuvastatin. In summary, daclatasvir is a hepatitis C virus, non-structural protein 5a-selective inhibitor with a well-characterized pharmacokinetic profile that forms part of potent and well-tolerated all-oral treatment regimens for chronic hepatitis C virus infection.
达卡他韦是一种新型、高度选择性的丙型肝炎病毒非结构蛋白 5A 聚合酶复制复合物抑制剂，具有皮摩尔效力和广泛的基因型覆盖范围。达卡他韦吸收迅速，单剂量递增研究中，达卡他韦的达峰时间为 1-2 小时，消除半衰期约为 10-14 小时。在多剂量递增研究中，第 4 天达到稳态。达卡他韦可不受食物或 pH 调节剂的影响而给药。达卡他韦在健康受试者和丙型肝炎病毒感染者中的暴露情况相似。年龄、种族或性别等内在因素不会影响达卡他韦的暴露情况。对于任何程度的肝或肾功能损害的患者，无需调整剂量。达卡他韦的清除率较低，主要通过细胞色素 P450 3A4 介导的代谢和 P-糖蛋白排泄以及肠分泌途径消除。达卡他韦的肾清除率是次要的消除途径。因此，当与强细胞色素 P450 3A4 抑制剂合用时，达卡他韦的剂量应从每日 60 毫克减少至 30 毫克。当与中度细胞色素 P450 3A4 抑制剂合用时，无需调整剂量。当与中度细胞色素 P450 3A4 诱导剂合用时，达卡他韦的剂量应从每日 60 毫克增加至 90 毫克。与强细胞色素 P450 3A4 诱导剂合用时，达卡他韦禁用。与 P-糖蛋白无抑制作用但对细胞色素 P450 3A4 有抑制作用的同时用药不太可能导致达卡他韦暴露的显著变化，因为达卡他韦的清除途径既包括细胞色素 P450 3A4，也包括 P-糖蛋白。达卡他韦对同时使用的细胞色素 P450 酶系统底物药物的药代动力学产生影响的可能性较低。体外研究表明，达卡他韦是一种弱至中度的转运蛋白抑制剂，包括有机阳离子转运蛋白 1、P-糖蛋白、有机转运多肽 1B1、有机转运多肽 1B3 和乳腺癌耐药蛋白，但在临床研究中，除了瑞舒伐他汀外，达卡他韦对同时使用的这些转运蛋白底物药物的药代动力学没有产生明显影响。综上所述，达卡他韦是一种丙型肝炎病毒非结构蛋白 5A 选择性抑制剂，具有特征明确的药代动力学特征，是治疗慢性丙型肝炎病毒感染的有效且耐受性良好的全口服治疗方案的一部分。
