Pfizer Global Research and Development, Groton, Connecticut, USA.
Clin Pharmacol Drug Dev. 2022 Dec;11(12):1447-1456. doi: 10.1002/cpdd.1163. Epub 2022 Aug 31.
Brepocitinib is a tyrosine kinase 2 and Janus kinase 1 inhibitor in development for treatment of inflammatory autoimmune diseases. This analysis aimed to add to the pharmacokinetic knowledge of the medication, through development of a population pharmacokinetic model and identification of factors that affect drug disposition. Plasma samples from 5 clinical trials were collated, composed of healthy volunteers, patients with psoriasis and patients with alopecia areata taking oral brepocitinib. NONMEM was used to develop a population pharmacokinetic model, and patient demographics were tested as covariates. The final model was a 1-compartment model with first-order absorption. The typical values for apparent clearance and apparent volume of distribution were 18.7 L/h (78% coefficient of variation [CV]) and 136 L (60.5% CV), respectively. Absorption was rapid with an absorption constant of 3.46 h, with an absorption lag of 0.24 hours observed with the oral tablet formulation. The proportional residual error was found to be 52.7% CV in healthy volunteers and 87.5% CV in patients. High-fat meals were associated with a reduction in both the rate (69.9% lower) and extent (28.3% lower) of absorption, while Asian populations had reduced clearance (24.3% lower). Nonlinear pharmacokinetics were observed at doses of 175 mg and above, with a 35.1% higher relative bioavailability at these doses. There were insufficient data to describe this nonlinearity as a continuous relationship. This initial description of the population pharmacokinetics will act as a foundation for the model-informed drug development of brepocitinib and will facilitate future modeling of this medicine. ClinicalTrials.gov numbers NCT02310750 NCT03236493 NCT03656952 NCT02969018 NCT02974868.
布罗匹替尼是一种酪氨酸激酶 2 和 Janus 激酶 1 抑制剂，目前正在开发用于治疗炎症性自身免疫性疾病。本分析旨在通过开发群体药代动力学模型和确定影响药物处置的因素，增加该药物的药代动力学知识。合并了来自 5 项临床试验的血浆样本，这些试验包括接受口服布罗匹替尼治疗的健康志愿者、银屑病患者和斑秃患者。NONMEM 用于开发群体药代动力学模型，并将患者人口统计学数据作为协变量进行测试。最终模型为 1 室模型，具有 1 阶吸收。表观清除率和表观分布容积的典型值分别为 18.7 L/h（78%变异系数[CV]）和 136 L（60.5% CV）。吸收迅速，吸收常数为 3.46 h，口服片剂制剂观察到吸收滞后 0.24 小时。在健康志愿者中，比例残差的 CV 为 52.7%，在患者中为 87.5%。高脂肪餐与吸收速率（降低 69.9%）和程度（降低 28.3%）均降低有关，而亚洲人群的清除率降低（降低 24.3%）。在 175 mg 及以上剂量时观察到非线性药代动力学，这些剂量的相对生物利用度增加 35.1%。没有足够的数据来描述这种非线性关系作为连续关系。该群体药代动力学的初步描述将作为布罗匹替尼模型指导药物开发的基础，并将促进该药物的未来建模。临床试验编号 NCT02310750 NCT03236493 NCT03656952 NCT02969018 NCT02974868。
