González-Sales Mario, Djebli Nassim, Meneses-Lorente Georgina, Buchheit Vincent, Bonnefois Guillaume, Tremblay Pierre-Olivier, Frey Nicolas, Mercier François
Modeling Great Solutions, Escaldes-Engordany, Andorra.
Roche Pharmaceutical Research and Early Development, Roche Innovation Center, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland.
Cancer Chemother Pharmacol. 2021 Dec;88(6):997-1007. doi: 10.1007/s00280-021-04353-8. Epub 2021 Sep 18.
Entrectinib (ROZLYTREK) is a CNS-active, potent, and selective inhibitor of ROS1, TRK A/B/C, and ALK kinase activity. It was recently approved for the treatment of ROS1-positive non-small cell lung cancer and NTRK gene fusion-positive solid tumors. The main objective of this analysis was to characterize the pharmacokinetics (PK) of entrectinib and its main active metabolite, M5.
A total of 276 cancer patients receiving oral entrectinib were included in the analysis. A model-based population approach was used to characterize the PK profiles of both entities using NONMEM 7.4. A joint model captures the PK of both entrectinib and M5. The effects of pH modifiers, formulation, weight, age, and sex on model parameters were assessed. Model performance was evaluated using visual predictive checks (VPCs).
The absorption of entrectinib was best described using a sequential zero- and first-order absorption model and the disposition with one-compartment model for each entity with linear elimination. Moderate-to-high between-patient variability was estimated in model parameters (from 30.8% for the apparent clearance of entrectinib to 122% for the first-order absorption rate constant). Theory-based allometric scaling using body weight on clearances and volumes and a 28% lower relative bioavailability of the F1 formulation in pediatric patients were retained in the model. The VPC confirmed the good predictive performance of the PopPK model.
A robust population PK model was built and qualified for entrectinib and M5, describing linear PK for both entities. This model was used to support the ROZLYTREK new drug application.
恩曲替尼（ROZLYTREK）是一种具有中枢神经系统活性的、强效且选择性的ROS1、TRK A/B/C和ALK激酶活性抑制剂。它最近被批准用于治疗ROS1阳性非小细胞肺癌和NTRK基因融合阳性实体瘤。本分析的主要目的是表征恩曲替尼及其主要活性代谢物M5的药代动力学（PK）特征。
共有276例接受口服恩曲替尼的癌症患者纳入分析。采用基于模型的群体方法，使用NONMEM 7.4来表征这两种物质的PK特征。一个联合模型可捕捉恩曲替尼和M5的PK情况。评估了pH调节剂、制剂、体重、年龄和性别对模型参数的影响。使用视觉预测检查（VPC）评估模型性能。
恩曲替尼的吸收情况最好用序贯零级和一级吸收模型来描述，其处置情况则用每个实体具有线性消除的单室模型来描述。模型参数中估计出患者间存在中度到高度的变异性（从恩曲替尼的表观清除率的30.8%到一级吸收速率常数的122%）。基于理论的异速生长标度法，即使用体重对清除率和体积进行标度，以及儿科患者中F1制剂相对生物利用度低28%的情况被保留在模型中。VPC证实了群体药代动力学（PopPK）模型具有良好的预测性能。
建立了一个稳健的群体PK模型，并对恩曲替尼和M5进行了验证，该模型描述了这两种物质的线性PK特征。该模型用于支持ROZLYTREK的新药申请。
