Genentech Inc., South San Francisco, CA, USA.
Clinical Pharmacology, Genentech Research and Early Development, 1 DNA Way, MS463a, South San Francisco, CA, 94080, USA.
Clin Pharmacokinet. 2019 Dec;58(12):1621-1634. doi: 10.1007/s40262-019-00788-8.
Venetoclax is a selective B-cell lymphoma-2 (BCL-2) inhibitor approved for use as monotherapy or with rituximab in patients with chronic lymphocytic leukemia (CLL). The objectives of the current analysis of observed data from adult patients randomized to venetoclax-rituximab in the phase III MURANO study were to characterize venetoclax pharmacokinetics (PKs) using a Bayesian approach, evaluate whether a previously developed population PK model for venetoclax can describe the PKs of venetoclax when administered with rituximab, and to determine post hoc estimates of PK parameters for the exposure-response analysis.
Parameter estimates and uncertainty estimated by a population PK model were used as priors. Additional covariate effects (CLL risk status, geographic region, and 17p deletion [del(17p)] status) were added to the model. The updated model was used to describe venetoclax PKs after repeated dosing in combination with rituximab, and to determine post hoc estimates of PK parameters for exposure-response analysis.
The PK analysis included 600 quantifiable venetoclax PK samples from 182 patients in the MURANO study. Model evaluation using standard diagnostic plots, visual predictive checks, and normalized prediction distribution error plots indicated no model deficiencies. There was no significant relationship between venetoclax apparent clearance (CL/F) and bodyweight, age, sex, mild and moderate hepatic and renal impairment, or coadministration of weak cytochrome P450 3A inhibitors. The chromosomal abnormality del(17p) and CLL risk status had no apparent effect on the PKs of venetoclax. A minimal increase in venetoclax CL/F (approximately 7%) was observed after coadministration with rituximab. CL/F was 30% lower in patients from Central and Eastern Europe (n = 60) or Asia (n = 4) compared with other regions (95% confidence interval [CI] 21-39%). Apparent central volume of distribution was 30% lower (95% CI 22-38%) in females (n = 56) compared with males (n = 126). No clinically significant impact of region or sex was observed on key safety and efficacy outcomes.
The Bayesian model successfully characterized venetoclax PKs over time and confirmed key covariates affecting PKs in the MURANO study. The model was deemed appropriate for further use in simulations and for generating individual patient PK parameters for subsequent exposure-response evaluation.
维奈托克是一种选择性 B 细胞淋巴瘤-2（BCL-2）抑制剂，已被批准用于治疗慢性淋巴细胞白血病（CLL）患者的单药治疗或与利妥昔单抗联合治疗。本项对 III 期 MURANO 研究中接受维奈托克-利妥昔单抗随机分组的成年患者的观察数据进行的分析，旨在采用贝叶斯方法描述维奈托克的药代动力学（PK），评估先前开发的维奈托克群体 PK 模型是否可以描述维奈托克与利妥昔单抗联合给药时的 PK，以及确定事后估计 PK 参数用于暴露-反应分析。
使用群体 PK 模型估计的参数和不确定性作为先验信息。将额外的协变量效应（CLL 风险状态、地理位置和 17p 缺失[del（17p）]状态）添加到模型中。使用更新后的模型描述重复给药时与利妥昔单抗联合使用的维奈托克 PK，并确定事后估计 PK 参数用于暴露-反应分析。
本 PK 分析纳入了 MURANO 研究中 182 名患者的 600 份可量化的维奈托克 PK 样本。使用标准诊断图、可视化预测检查和归一化预测分布误差图进行模型评估，表明模型无缺陷。维奈托克表观清除率（CL/F）与体重、年龄、性别、轻度和中度肝肾功能损害或同时使用弱细胞色素 P450 3A 抑制剂之间无显著关系。染色体异常 del（17p）和 CLL 风险状态对维奈托克 PK 无明显影响。与利妥昔单抗联合给药后，维奈托克 CL/F 观察到轻微增加（约 7%）。来自中欧和东欧（n=60）或亚洲（n=4）的患者与其他地区（95%置信区间 [CI]21-39%）相比，维奈托克 CL/F 降低 30%（95%CI21-39%）。女性（n=56）的表观中央分布容积比男性（n=126）低 30%（95%CI22-38%）。在关键安全性和疗效终点方面，未观察到地区或性别的临床显著影响。
贝叶斯模型成功地描述了维奈托克随时间的 PK，并确认了 MURANO 研究中影响 PK 的关键协变量。该模型被认为适合进一步用于模拟和生成后续暴露-反应评估的个体患者 PK 参数。
