在健康受试者和类风湿关节炎受试者中的乌帕替尼的群体药代动力学：I 期和 II 期临床试验分析。
Population Pharmacokinetics of Upadacitinib in Healthy Subjects and Subjects with Rheumatoid Arthritis: Analyses of Phase I and II Clinical Trials.
机构信息
AbbVie Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen am Rhein, Germany.
AbbVie Clinical Pharmacology and Pharmacometrics, AbbVie, 1 North Waukegan Road, Bldg. AP31-3, North Chicago, IL, 60064, USA.
出版信息
Clin Pharmacokinet. 2018 Aug;57(8):977-988. doi: 10.1007/s40262-017-0605-6.
BACKGROUND AND OBJECTIVES
Upadacitinib is a janus kinase (JAK) 1 inhibitor being developed for the treatment of rheumatoid arthritis (RA) and other inflammatory diseases. This work characterized upadacitinib population pharmacokinetics in healthy subjects and RA patients and the effects of covariates on upadacitinib exposure.
METHODS
Upadacitinib plasma concentrations (n = 6399) from 107 healthy subjects and 466 RA patients from three phase I and two 12-week RA phase IIb trials (1-48 mg immediate-release doses across studies) were analyzed using non-linear mixed-effects modeling. The models were qualified using bootstrap and stochastic simulations.
RESULTS
A two-compartment model with first-order absorption and elimination described upadacitinib pharmacokinetics. Estimates (95% bootstrap confidence interval) for upadacitinib oral clearance, steady-state volume of distribution, absorption lag time, and mean absorption time were 39.7 (37.8-41.5) L/h, 210 (196-231) L, 0.48 (0.47-0.49) h, and 0.08 (0.04-0.12) h, respectively, for a typical healthy male. Matching on other covariates, a 16 and 32% higher upadacitinib area under the concentration-time curve (AUC) was estimated for females relative to males, and for subjects with RA relative to healthy volunteers, respectively. Subjects with RA with mild or moderate renal impairment were estimated to have 16 and 32% higher upadacitinib AUC, respectively, compared with subjects with RA with normal renal function. Upadacitinib clearance was not correlated with body weight.
CONCLUSIONS
Upadacitinib pharmacokinetics follow dose-proportional, bi-exponential disposition. A slightly lower upadacitinib clearance is estimated in subjects with RA than in healthy volunteers, consistent with observations for other JAK inhibitors. Other covariates (weight, sex, mild or moderate renal impairment) are not associated with clinically relevant effects on upadacitinib exposure.
TRIAL REGISTRATION
ClinicalTrials.gov ( https://clinicaltrials.gov/ ) identifiers: NCT01741493, NCT02066389, and NCT01960855.
背景和目的
Upadacitinib 是一种 Janus 激酶（JAK）1 抑制剂，目前正处于开发阶段，用于治疗类风湿关节炎（RA）和其他炎症性疾病。本研究旨在对健康受试者和 RA 患者的 Upadacitinib 群体药代动力学特征进行描述，并对其影响因素进行分析。
方法
本研究对来自三项 I 期和两项 12 周 RA IIb 期研究（研究中共有 1-48mg 速释剂量）的 107 名健康受试者和 466 名 RA 患者的 Upadacitinib 血浆浓度（n=6399）进行了分析，采用非线性混合效应模型进行分析。使用 Bootstrap 和随机模拟对模型进行了验证。
结果
采用具有一级吸收和消除的二室模型描述了 Upadacitinib 的药代动力学特征。估算的 Upadacitinib 口服清除率、稳态分布容积、吸收滞后时间和平均吸收时间分别为 39.7（37.8-41.5）L/h、210（196-231）L、0.48（0.47-0.49）h 和 0.08（0.04-0.12）h，这些参数是针对典型的健康男性估算的。与男性相比，女性的 Upadacitinib 曲线下面积（AUC）估计值高出 16%和 32%，而 RA 患者的 AUC 估计值则比健康志愿者高出 32%。与肾功能正常的 RA 患者相比，轻度或中度肾功能不全的 RA 患者的 Upadacitinib AUC 分别高出 16%和 32%。Upadacitinib 清除率与体重无关。
结论
Upadacitinib 的药代动力学呈剂量比例、双指数分布。与其他 JAK 抑制剂的观察结果一致，RA 患者的 Upadacitinib 清除率略低于健康志愿者。其他影响因素（体重、性别、轻度或中度肾功能不全）与 Upadacitinib 暴露量无临床相关影响。
临床试验注册
ClinicalTrials.gov（https://clinicaltrials.gov/）标识符：NCT01741493、NCT02066389 和 NCT01960855。
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