Astellas Pharma Inc, Tokyo, Japan.
Pharmacol Res Perspect. 2021 May;9(3):e00744. doi: 10.1002/prp2.744.
The aim was to analyze the relationship between peficitinib exposure and efficacy response according to American College of Rheumatology (ACR) 20 criteria and 28-joint disease activity score based on C-reactive protein (DAS28-CRP) in rheumatoid arthritis (RA) patients, and to identify relevant covariates by developing exposure-response models. The analysis incorporated results from three multicenter, placebo-controlled, double-blind studies. As an exposure parameter, individual post hoc pharmacokinetic (PK) parameters were obtained from a previously constructed population PK model. Longitudinal ACR20 response rate and individual longitudinal DAS28-CRP measurements were modeled by a non-linear mixed effect model. Influential covariates were explored, and their effects on efficacy were quantitatively assessed and compared. The exposure-response models of effect of peficitinib on duration-dependent increase in ACR20 response rate and decrease in DAS28-CRP were adequately described by a continuous time Markov model and an indirect response model, respectively, with a sigmoidal E saturable of drug exposure in RA patients. The significant covariates were DAS28-CRP and total bilirubin at baseline for the ACR20 response model, and CRP at baseline and concomitant methotrexate treatment for the DAS28-CRP model. The covariate effects were highly consistent between the two models. Our exposure-response models of peficitinib in RA patients satisfactorily described duration-dependent improvements in ACR20 response rates and DAS28-CRP measurements, and provided consistent covariate effects. Only the ACR20 model incorporated a patient's subjective high expectations just after the start of the treatment. Therefore, due to their similarities and differences, both models may have relevant applications in the development of RA treatment. CLINICAL TRIAL REGISTRATION: NCT01649999 (RAJ1), NCT02308163 (RAJ3), NCT02305849 (RAJ4).
目的是根据美国风湿病学会（ACR）20 标准和基于 C 反应蛋白（DAS28-CRP）的 28 关节疾病活动评分（DAS28-CRP），分析培非替尼暴露与类风湿关节炎（RA）患者疗效反应之间的关系，并通过开发暴露-反应模型确定相关协变量。该分析纳入了三项多中心、安慰剂对照、双盲研究的结果。作为暴露参数，个体事后药代动力学（PK）参数是从先前构建的群体 PK 模型中获得的。通过非线性混合效应模型对 ACR20 反应率的纵向和个体纵向 DAS28-CRP 测量进行建模。探讨了有影响的协变量，并对其对疗效的影响进行了定量评估和比较。培非替尼对 ACR20 反应率随时间依赖性增加和 DAS28-CRP 降低的疗效的暴露-反应模型分别由连续时间马尔可夫模型和间接反应模型充分描述，RA 患者的药物暴露具有 sigmoidal E 饱和。显著的协变量是 ACR20 反应模型中的 DAS28-CRP 和基线总胆红素，以及 DAS28-CRP 模型中的 CRP 和伴随的甲氨蝶呤治疗。两个模型中的协变量效应高度一致。我们对 RA 患者培非替尼的暴露-反应模型很好地描述了 ACR20 反应率和 DAS28-CRP 测量值随时间的改善，并提供了一致的协变量效应。只有 ACR20 模型纳入了患者在治疗开始后不久的主观高期望。因此，由于它们的相似性和差异，两个模型都可能在 RA 治疗的开发中具有相关应用。临床试验注册：NCT01649999（RAJ1）、NCT02308163（RAJ3）、NCT02305849（RAJ4）。
