Population pharmacokinetic analyses of pozelimab in patients with CD55-deficient protein-losing enteropathy (CHAPLE disease).

IF 2.2 4区 医学 Q3 PHARMACOLOGY & PHARMACY Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2024-12-01 Epub Date: 2024-09-30 DOI:10.1007/s10928-024-09941-8
Kuan-Ju Lin, Jeanne Mendell, John D Davis, Lutz O Harnisch
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Abstract

Pozelimab, a monoclonal antibody directed against C5, is the first and only treatment for adult and pediatric patients (≥ 1 year) with CD55-deficient protein-losing enteropathy (CHAPLE) disease. A target-mediated drug disposition (TMDD) population pharmacokinetic (PopPK) model was developed using pooled data from four phase 1-3 studies to characterize the pharmacokinetics (PK) of total pozelimab and total C5, and to simulate free pozelimab and free C5 to support the dose regimen in patients with CHAPLE disease. A TMDD PopPK model was developed using total pozelimab and total C5 concentration-time data from 106 participants (82 healthy volunteers; 24 patients with paroxysmal nocturnal hemoglobinuria [PNH]). This model was refined and updated to include PK data from 10 patients with CHAPLE disease from a phase 2/3 study. Stochastic simulations predicted concentration-time profiles for total pozelimab, free pozelimab, and free C5, to obtain pozelimab exposure metrics for patients with CHAPLE disease. A two-compartment TMDD model with two binding sites based on the quasi-equilibrium approximation adequately described the concentration-time profiles of total pozelimab and total C5. Body weight was identified as the most important source of pozelimab PK variability; therefore, the dose was adjusted based on body weight for the predominantly pediatric patients with CHAPLE disease. A robust TMDD PopPK model was developed to describe the PK of total pozelimab and total C5 following pozelimab administration. Reliable predictions for individual exposures of total pozelimab and free C5 were possible and supported the 10 mg/kg weight-based dose regimen in patients with CHAPLE disease.

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波珠单抗在 CD55 缺乏性蛋白失代偿性肠病(CHAPLE 病)患者中的群体药代动力学分析。
波珠单抗是一种针对 C5 的单克隆抗体,是 CD55 缺乏性蛋白丢失性肠病(CHAPLE)成人和儿童患者(≥ 1 岁)的第一种也是唯一一种治疗方法。利用四项 1-3 期研究的汇总数据建立了靶向介导药物处置(TMDD)群体药代动力学(PopPK)模型,以描述总波珠单抗和总 C5 的药代动力学(PK)特征,并模拟游离波珠单抗和游离 C5,为 CHAPLE 疾病患者的剂量方案提供支持。利用 106 名参与者(82 名健康志愿者;24 名阵发性夜间血红蛋白尿患者 [PNH])的总波珠单抗和总 C5 浓度-时间数据,建立了 TMDD PopPK 模型。对该模型进行了改进和更新,纳入了一项 2/3 期研究中 10 名 CHAPLE 患者的 PK 数据。随机模拟预测了总泊珠利单抗、游离泊珠利单抗和游离 C5 的浓度-时间曲线,以获得 CHAPLE 疾病患者的泊珠利单抗暴露指标。根据准平衡近似法建立的具有两个结合位点的两室 TMDD 模型充分描述了总泊珠利单抗和总 C5 的浓度-时间曲线。体重被认为是波珠利单抗 PK 变异的最重要来源;因此,对于主要患有 CHAPLE 疾病的儿科患者,剂量是根据体重进行调整的。我们建立了一个稳健的 TMDD PopPK 模型来描述波珠单抗给药后总波珠单抗和总 C5 的 PK。对总泊珠利单抗和游离C5的个体暴露量进行可靠预测是可能的,并支持在CHAPLE病患者中采用基于体重的10毫克/千克剂量方案。
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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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