Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, Illinois, USA.
Department of Statistics, AbbVie Inc., North Chicago, Illinois, USA.
J Clin Pharmacol. 2020 Jan;60(1):86-95. doi: 10.1002/jcph.1496. Epub 2019 Aug 5.
The aim of this study was to characterize the effects of upadacitinib, a Janus kinase 1 inhibitor, on in vivo activity of different cytochrome P450 (CYP) enzymes using a cocktail approach. Healthy subjects (n = 20) received single oral doses of the modified Cooperstown 5+1 cocktail drugs (midazolam [CYP3A], caffeine [CYP1A2], warfarin + vitamin K [CYP2C9], omeprazole [CYP2C19], and dextromethorphan [CYP2D6]) without upadacitinib and on day 11 (midazolam) or 12 (all other probes) of a 15-day regimen of upadacitinib 30 mg once daily (extended-release formulation). Serial blood samples and 12-hour urine samples were collected for assays of the probe substrates and select metabolites. The ratio (90%CI) of area under the plasma concentration-time curve from time 0 to infinity (AUC ) central values when the cocktail drugs were administered with upadacitinib relative to when administered alone were 0.74 (0.68-0.80) for midazolam, 1.22 (1.15-1.29) for caffeine, 1.11 (1.07-1.15) for S-warfarin, 1.07 (0.95-1.22) for dextromethorphan, and 0.82 (0.72-0.94) for omeprazole. The ratio (90%CI) was 1.09 (1.00-1.19) for 5-hydroxy-omeprazole to omeprazole AUC ratio and 1.17 (0.97-1.41) for dextromethorphan to dextrorphan 12-hour molar urinary ratio. Upadacitinib 30 mg once daily (a dose that is twice the optimal dose in rheumatoid arthritis based on phase 3 results) has a limited effect on CYP3A activity (26% decrease in exposure of midazolam, a sensitive CYP3A substrate) and no relevant effects on CYP1A2, CYP2C9, CYP2C19, or CYP2D6 activity in vivo. No clinically relevant changes in plasma exposures are expected for drugs that are substrates for the evaluated CYP enzymes when coadministered with upadacitinib.
本研究旨在采用鸡尾酒方法，研究一种 Janus 激酶 1 抑制剂（upadacitinib）对不同细胞色素 P450（CYP）酶体内活性的影响。20 名健康受试者接受了单次口服改良库珀斯敦 5+1 鸡尾酒药物（咪达唑仑[CYP3A]、咖啡因[CYP1A2]、华法林+维生素 K[CYP2C9]、奥美拉唑[CYP2C19]和右美沙芬[CYP2D6]），未服用 upadacitinib；并在服用 upadacitinib 30mg 每日一次（延长释放制剂）的 15 天疗程第 11 天（咪达唑仑）或第 12 天（所有其他探针）时服用。连续采集血样和 12 小时尿液样本来检测探针底物和选定的代谢物。与单独给药时相比，当鸡尾酒药物与 upadacitinib 联合给药时，探针药物的中心 AUC 比值（90%CI）分别为：咪达唑仑为 0.74（0.68-0.80），咖啡因为 1.22（1.15-1.29），S-华法林为 1.11（1.07-1.15），右美沙芬为 1.07（0.95-1.22），奥美拉唑为 0.82（0.72-0.94）。5-羟奥美拉唑与奥美拉唑 AUC 比值的比值（90%CI）为 1.09（1.00-1.19），右美沙芬与右美沙芬 12 小时摩尔尿比值的比值为 1.17（0.97-1.41）。每日一次 30mg upadacitinib（基于 3 期结果，这是类风湿关节炎的最佳剂量的两倍）对 CYP3A 活性（咪达唑仑的暴露量减少 26%，咪达唑仑是一种敏感的 CYP3A 底物）仅有有限的影响，对体内 CYP1A2、CYP2C9、CYP2C19 或 CYP2D6 活性无相关影响。当与 upadacitinib 同时给药时，预计对于评估的 CYP 酶的底物药物，不会出现血浆暴露的临床相关变化。
