Employing zero-inflated beta distribution in an exposure-response analysis of TYK2/JAK1 inhibitor brepocitinib in patients with plaque psoriasis

IF 2.2 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Nikolaos Tsamandouras, Ruolun Qiu, Jim H. Hughes, Kevin Sweeney, John P. Prybylski, Christopher Banfield, Timothy Nicholas
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Abstract

Brepocitinib is an oral selective dual TYK2/JAK1 inhibitor and based on its cytokine inhibition profile is expected to provide therapeutic benefit in the treatment of plaque psoriasis. Efficacy data from a completed Phase 2a study in patients with moderate-to-severe plaque psoriasis were utilized to develop a population exposure-response model that can be employed to inform dose selection decisions for further clinical development. A modeling approach that employs the zero-inflated beta distribution was used to account for the bounded nature and distributional characteristics of the Psoriasis Area and Severity Index (PASI) score data. The developed exposure-response model provided an adequate description of the observed PASI scores across all the treatment arms tested and across both the induction and maintenance dosing periods of the study. In addition, the developed model exhibited a good predictive capacity with regard to the derived responder metrics (e.g., 75%/90%/100% improvement in PASI score [PASI75/90/100]). Clinical trial simulations indicated that the induction/maintenance dosing paradigm explored in this study does not offer any advantages from an efficacy perspective and that doses of 10, 30, and 60 mg once-daily may be suitable candidates for clinical evaluation in subsequent Phase 2b studies.

Abstract Image

在对斑块状银屑病患者使用 TYK2/JAK1 抑制剂 brepocitinib 进行暴露-反应分析时采用零膨胀贝塔分布
Brepocitinib 是一种口服选择性 TYK2/JAK1 双抑制剂,根据其细胞因子抑制特征,有望为斑块状银屑病的治疗带来疗效。我们利用已完成的中重度斑块状银屑病患者 2a 期研究的疗效数据开发了一个群体暴露-反应模型,该模型可为进一步临床开发的剂量选择决策提供依据。该模型采用了零膨胀贝塔分布的建模方法,以考虑银屑病面积和严重程度指数(PASI)评分数据的约束性和分布特征。所建立的暴露-反应模型充分描述了在所有接受测试的治疗组中以及在研究的诱导期和维持期中观察到的 PASI 分数。此外,所开发的模型对衍生的应答指标(如 PASI 评分改善 75%/90%/100% [PASI75/90/100])具有良好的预测能力。临床试验模拟表明,从疗效角度来看,本研究中探索的诱导/维持剂量范例并不具有任何优势,而每日一次的 10、30 和 60 毫克剂量可能适合在随后的 2b 期研究中进行临床评估。
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来源期刊
CiteScore
4.90
自引率
4.00%
发文量
39
审稿时长
6-12 weeks
期刊介绍: Broadly speaking, the Journal of Pharmacokinetics and Pharmacodynamics covers the area of pharmacometrics. The journal is devoted to illustrating the importance of pharmacokinetics, pharmacodynamics, and pharmacometrics in drug development, clinical care, and the understanding of drug action. The journal publishes on a variety of topics related to pharmacometrics, including, but not limited to, clinical, experimental, and theoretical papers examining the kinetics of drug disposition and effects of drug action in humans, animals, in vitro, or in silico; modeling and simulation methodology, including optimal design; precision medicine; systems pharmacology; and mathematical pharmacology (including computational biology, bioengineering, and biophysics related to pharmacology, pharmacokinetics, orpharmacodynamics). Clinical papers that include population pharmacokinetic-pharmacodynamic relationships are welcome. The journal actively invites and promotes up-and-coming areas of pharmacometric research, such as real-world evidence, quality of life analyses, and artificial intelligence. The Journal of Pharmacokinetics and Pharmacodynamics is an official journal of the International Society of Pharmacometrics.
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