Xie Rujia, Deng Chenhui, Wang Qiang, Kanik Keith S, Nicholas Timothy, Menon Sujatha
Int J Clin Pharmacol Ther. 2019 Sep;57(9):464-473. doi: 10.5414/CP203516.
Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). This analysis characterized the pharmacokinetics (PK) of tofacitinib in adult patients with active PsA and evaluated the impact of covariates (baseline characteristics) on the disposition of tofacitinib.
Data were pooled from two phase 3 studies of tofacitinib of up to 12 months' duration in patients with active PsA (OPAL Broaden (NCT01877668); OPAL Beyond (NCT01882439)). This analysis included 650 tofacitinib-treated patients with 3,252 tofacitinib plasma concentration measurements. Tofacitinib PK was described using a one-compartment disposition model parameterized in terms of apparent oral clearance (CL/F) and apparent volume of distribution (V/F) with first-order absorption rate (Ka) and a lag time. Covariates evaluated were baseline age, baseline body weight, sex, race, ethnicity, baseline creatinine clearance (BCCL), and baseline C-reactive protein.
The estimates (95% confidence interval) of PK model parameters of a reference patient were CL/F: 20.4 (18.6, 21.8) L/h; V/F: 110 (108, 113) L; and Ka: 13.8 (12.1, 16.6)/h. Among the covariates, only BCCL led to clinically relevant changes in exposure; however, this was consistent with the known contribution of renal excretion to the total clearance of tofacitinib (~ 30%).
Tofacitinib did not require dose modification or restrictions for age, body weight, sex, race, ethnicity, or baseline disease severity in patients with active PsA based on the magnitude of exposure relative to a reference patient. Dosing adjustments for renal impairment were derived from a separate phase 1 study.
托法替布是一种口服的Janus激酶抑制剂，用于治疗银屑病关节炎（PsA）。本分析旨在描述托法替布在活动性PsA成年患者中的药代动力学（PK）特征，并评估协变量（基线特征）对托法替布处置的影响。
数据来自两项托法替布的3期研究，研究对象为活动性PsA患者，研究时长最长为12个月（OPAL Broaden（NCT01877668）；OPAL Beyond（NCT01882439））。本分析纳入了650例接受托法替布治疗的患者，共进行了3252次托法替布血浆浓度测量。托法替布的PK用单室处置模型描述，该模型根据表观口服清除率（CL/F）、表观分布容积（V/F）、一级吸收速率（Ka）和滞后时间进行参数化。评估的协变量包括基线年龄、基线体重、性别、种族、民族、基线肌酐清除率（BCCL）和基线C反应蛋白。
参考患者PK模型参数的估计值（95%置信区间）为：CL/F：20.4（18.6，21.8）L/h；V/F：110（108，113）L；Ka：13.8（12.1，16.6）/h。在这些协变量中，只有BCCL导致了暴露方面具有临床意义的变化；然而，这与已知的肾脏排泄对托法替布总清除率的贡献（约30%）一致。
基于与参考患者相比的暴露程度，活动性PsA患者使用托法替布时，无需因年龄、体重、性别、种族、民族或基线疾病严重程度而调整剂量或进行限制。针对肾功能损害的剂量调整来自另一项1期研究。
