Jiangsu Hengrui Medicine Co. Ltd. Lianyungang, Shanghai, People's Republic of China.
Department of Pharmacy, The Third Hospital of Changsha, Changsha, People's Republic of China.
Br J Clin Pharmacol. 2023 Aug;89(8):2561-2568. doi: 10.1111/bcp.15733. Epub 2023 Apr 17.
SHR0302 is a selective Janus kinase (JAK) 1 inhibitor under clinical investigation for the treatment of rheumatoid arthritis (RA). As SHR0302 is metabolized mainly by cytochrome P450 (CYP) 3A4, clinical studies were performed to evaluate the effects of a strong CYP3A4 inducer, rifampin, and a strong CYP3A4 inhibitor, itraconazole, on the pharmacokinetics of SHR0302 in healthy subjects.
Two phase I, open-label, fixed-sequence drug interaction studies enrolled 28 subjects. In Study A, 14 subjects received 8 mg SHR0302 on Days 1 and 10, and 600 mg rifampin once daily on Days 3-11. In Study B, 14 subjects received 4 mg SHR0302 on Days 1 and 8, and 200 mg itraconazole once daily on Days 4-10. Blood samples were collected to measure SHR0302 concentrations. Pharmacokinetic parameters were calculated using non-compartmental analysis. Treatment comparisons were made using mixed-effect models.
Co-administration with rifampin decreased the exposures of SHR0302 with geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for AUC of 0.51 (0.49, 0.54) and C of 0.91 (0.84, 0.98). Co-administration with itraconazole increased the exposures of SHR0302 with GMR (90% CIs) for AUC of 1.48 (1.41, 1.56) and C of 1.06 (0.982, 1.14). Single oral doses of SHR0302 administered with or without rifampin or itraconazole were generally safe.
Strong CYP3A4 induction and inhibition both resulted in a weak effect on the clinical exposures of SHR0302. These present studies provided valuable information that helps inform SHR0302 dosing instructions and concomitant medication precautions.
SHR0302 是一种临床研究用于治疗类风湿关节炎（RA）的选择性 Janus 激酶（JAK）1 抑制剂。由于 SHR0302 主要通过细胞色素 P450（CYP）3A4 代谢，因此进行了临床研究以评估强 CYP3A4 诱导剂利福平（rifampin）和强 CYP3A4 抑制剂伊曲康唑（itraconazole）对健康受试者中 SHR0302 药代动力学的影响。
两项 I 期、开放标签、固定序列药物相互作用研究共纳入 28 名受试者。在研究 A 中，14 名受试者于第 1 天和第 10 天接受 8mg SHR0302，并于第 3-11 天每天接受 600mg 利福平。在研究 B 中，14 名受试者于第 1 天和第 8 天接受 4mg SHR0302，并于第 4-10 天每天接受 200mg 伊曲康唑。采集血样以测量 SHR0302 浓度。采用非房室分析计算药代动力学参数。采用混合效应模型进行治疗比较。
与利福平联合给药使 SHR0302 的暴露量降低，AUC 的几何均数比值（GMR）（90%置信区间[CI]）为 0.51（0.49，0.54），C 的 GMR 为 0.91（0.84，0.98）。与伊曲康唑联合给药使 SHR0302 的暴露量增加，AUC 的 GMR（90%CI）为 1.48（1.41，1.56），C 的 GMR 为 1.06（0.982，1.14）。与利福平或伊曲康唑联合或不联合使用时，单次口服 SHR0302 通常是安全的。
强 CYP3A4 诱导和抑制均对 SHR0302 的临床暴露量产生弱影响。这些研究提供了有价值的信息，有助于确定 SHR0302 的给药说明和伴随药物注意事项。
