Population Pharmacokinetics of Epcoritamab Following Subcutaneous Administration in Relapsed or Refractory B Cell Non-Hodgkin Lymphoma.

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Clinical Pharmacokinetics Pub Date : 2025-01-01 Epub Date: 2024-12-21 DOI:10.1007/s40262-024-01464-2
Tommy Li, Leonid Gibiansky, Apurvasena Parikh, Marcel van der Linden, Kinjal Sanghavi, Matthew Putnins, Mariana Sacchi, Huaibao Feng, Tahamtan Ahmadi, Manish Gupta, Steven Xu
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引用次数: 0

Abstract

Background and objectives: Epcoritamab is a CD3xCD20 bispecific antibody approved for the treatment of adults with different types of relapsed or refractory (R/R) B cell non-Hodgkin lymphoma (B-NHL) after ≥ 2 lines of systemic therapy. Here we report the first results from a population pharmacokinetic model-based analysis using data from 2 phase 1/2 clinical trials (EPCORE® NHL-1, NCT03625037 and EPCORE NHL-3, NCT04542824) evaluating epcoritamab in patients with R/R B-NHL.

Methods: Plasma concentration-time data included 6819 quantifiable pharmacokinetic samples from 327 patients with R/R B-NHL. A wide range of subcutaneous epcoritamab doses, 0.004-60 mg, was explored, with most patients (n = 298) following the approved dosing regimen: step-up dose (SUD) 1 of 0.16 mg on cycle 1 day 1 and SUD 2 of 0.8 mg on cycle 1 day 8, followed by a full dose of 48 mg administered weekly during cycles 1-3, biweekly in cycles 4-9, and every 4 weeks thereafter. Each cycle lasted 28 days. The data were analyzed using nonlinear mixed-effects modeling.

Results: Quasisteady-state approximation of a two-compartment target-mediated drug disposition model with first-order absorption adequately characterized pharmacokinetics of epcoritamab following subcutaneous administration. After the first full dose and at the end of the weekly dosing regimen (end of cycle 3), the estimated median time to maximum concentration (tmax) was 4 and 2.3 days, respectively. Age and body weight were significant covariates on the pharmacokinetics of epcoritamab. The geometric mean (coefficient of variation [CV], %) of the apparent total volume of distribution was 25.6 L (82%) for patients with R/R large B cell lymphoma in EPCORE NHL-1. Epcoritamab elimination exhibited nonlinear characteristics, with exposure increasing more than proportionally over 1.5-48 mg doses. The geometric mean (CV%) values of apparent total clearance and terminal half-life were 0.53 L/day (40%) and 22 days (58%), respectively, at the end of cycle 3 for the 48 mg full dose. Clinical data analyses did not identify any association between assessed characteristics, including body weight or age, and clinical efficacy or safety. After accounting for body weight, no clinically significant differences in epcoritamab pharmacokinetics were observed for sex, race, renal or hepatic function, or other disease characteristics. Age was not found to significantly affect epcoritamab pharmacokinetic exposure. Antidrug antibodies developed in 4 (2.6%) of 156 evaluable patients treated with the approved 0.16/0.8/48 mg regimen. Antidrug antibody status did not affect epcoritamab pharmacokinetics.

Conclusions: Epcoritamab pharmacokinetics in R/R B-NHL were well characterized by the population pharmacokinetic model. No dosage adjustments are recommended in subpopulations based on body weight, age, sex, race, mild-to-moderate renal impairment, or mild hepatic impairment. The risk of immunogenicity was low. These are the first published results of population pharmacokinetic modeling for epcoritamab.

复发或难治性B细胞非霍奇金淋巴瘤皮下给药后依可利单抗的群体药代动力学。
背景和目的:Epcoritamab是一种CD3xCD20双特异性抗体,被批准用于治疗不同类型复发或难治性(R/R) B细胞非霍奇金淋巴瘤(B- nhl)的成人患者,经过≥2线的全身治疗。在这里,我们报告了基于群体药代动力学模型分析的第一个结果,该分析使用了2项1/2期临床试验(EPCORE®NHL-1, NCT03625037和EPCORE NHL-3, NCT04542824)的数据,评估了epcoritamab在R/R B-NHL患者中的作用。方法:血浆浓度-时间数据包括327例R/R B-NHL患者的6819份可量化药代动力学样本。研究探索了广泛的皮下依普利他单抗剂量范围,0.004- 60mg,大多数患者(n = 298)遵循批准的给药方案:第1周期第1天增加剂量(SUD) 1 0.16 mg,第1周期第8天增加剂量(SUD 2 0.8 mg),然后在第1-3周期每周给药48 mg,第4-9周期每两周给药一次,之后每4周给药一次。每个周期28 d。采用非线性混合效应模型对数据进行分析。结果:具有一级吸收的双室靶介导药物处置模型的准稳态近似充分表征了依霉素单抗皮下给药后的药代动力学。在第一次全剂量后和每周给药方案结束时(第3周期结束),估计达到最大浓度的中位时间(tmax)分别为4天和2.3天。年龄和体重是影响依霉素单抗药代动力学的显著协变量。EPCORE NHL-1中R/R大B细胞淋巴瘤患者表观总分布容积的几何平均值(变异系数[CV], %)为25.6 L(82%)。Epcoritamab消除表现出非线性特征,在1.5-48 mg剂量范围内,暴露量增加超过比例。在第3周期结束时,48 mg全剂量的表观总清除率和终末半衰期的几何平均值(CV%)分别为0.53 L/天(40%)和22天(58%)。临床数据分析未发现评估特征(包括体重或年龄)与临床疗效或安全性之间存在任何关联。在考虑了体重因素后,未观察到在性别、种族、肾功能或肝功能或其他疾病特征方面,epcoritamab药代动力学的临床显著差异。年龄未发现显着影响表应单抗药代动力学暴露。接受批准的0.16/0.8/48 mg方案治疗的156例可评估患者中有4例(2.6%)出现抗药抗体。抗药抗体状态不影响依霉素单抗的药代动力学。结论:Epcoritamab在R/R B-NHL中的药代动力学可通过群体药代动力学模型表征。不建议基于体重、年龄、性别、种族、轻度至中度肾功能损害或轻度肝功能损害的亚群调整剂量。免疫原性风险低。这是首次发表的依霉素单抗群体药代动力学模型的结果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
8.80
自引率
4.40%
发文量
86
审稿时长
6-12 weeks
期刊介绍: Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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