Abstract：
Glecaprevir/pibrentasvir (GLE/PIB) is an approved guideline-recommended chronic hepatitis C virus infection treatment. GLE/PIB coadministration with ethinyl oestradiol (EE) is not recommended in current labels owing to a Phase 1 study observing Grade ≥2 alanine aminotransferase (ALT) elevation in 2 out of 12 healthy women cotreated for 11 days with GLE/PIB and oral contraceptive (OC) containing 35 μg/250 μg EE/norgestimate. No Grade ≥2 elevation was observed with low-dose (20 μg) EE (n = 14). This Phase 1 study examined safety/tolerability of GLE/PIB coadministered with an OC containing low-dose EE using a larger sample size and longer treatment duration. Healthy premenopausal women were treated with EE/levonorgestrel alone (20/100 μg, Cycles 1-2), followed by coadministration with GLE/PIB (300/120 mg; Cycles 3-4). A safety criterion of special interest was a confirmed Grade ≥2 ALT elevation (>3× upper normal limit). Adverse events (AEs) and study drugs concentrations were examined. Of 85 enrolled women, 72 initiated combined GLE/PIB + EE/levonorgestrel treatment, 66 completed the study and 19 discontinued prematurely (non-safety reason, n = 16; AE [deemed unelated to GLE/PIB], n = 3). No participant met the safety criterion of special interest of confirmed Grade ≥2 ALT elevation. No serious/Grade ≥3 AEs were reported. Study drug concentrations were within the expected ranges. GLE/PIB in combination with an OC containing low-dose EE was generally well tolerated with no confirmed Grade ≥2 ALT elevation and no evidence of drug-induced liver injury. No pattern to the reported AEs and no new safety issues were identified. This was a Phase 1 study of healthy volunteers, not a registered clinical trial.
摘要：
Glecaprevir/pibrentasvir（GLE/PIB）是批准的指南推荐的慢性丙型肝炎病毒感染治疗。目前的标签中不建议使用GLE/PIB与乙炔基雌二醇（EE）共同给药，因为1期研究观察到12名健康女性中有2名谷丙转氨酶（ALT）升高，其中GLE/PIB和口服避孕药（OC）含有35μg/250μgEE/norgestimal。低剂量（20μg）EE（n=14）未观察到≥2级升高。该1期研究使用更大的样本量和更长的治疗持续时间检查了GLE/PIB与含有低剂量EE的OC共同给药的安全性/耐受性。健康的绝经前妇女单独使用EE/左炔诺孕酮（20/100μg，周期1-2),然后与GLE/PIB共同给药(300/120mg;周期3-4)。特别感兴趣的安全标准是确认的≥2级ALT升高（>3×正常上限）。检查不良事件(AE)和研究药物浓度。在85名注册妇女中，72开始GLE/PIB+EE/左炔诺孕酮联合治疗，66人完成了研究，19人过早中止(非安全原因，n=16；AE[认为与GLE/PIB无关]，n=3)。没有参与者符合确认的≥2级ALT升高的特殊利益的安全标准。未报告严重/≥3级不良事件。研究药物浓度在预期范围内。GLE/PIB与含有低剂量EE的OC组合通常具有良好的耐受性，没有证实的≥2级ALT升高，也没有药物诱导的肝损伤的证据。没有报告的AE模式，也没有发现新的安全性问题。这是一项针对健康志愿者的第一阶段研究，不是注册的临床试验.
