Population pharmacokinetic analysis of entrectinib in pediatric and adult patients with advanced/metastatic solid tumors: support of new drug application submission

Purpose Entrectinib (ROZLYTREK (R)) 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. Methods 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 (R) 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). Results 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. Conclusions 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 (R) new drug application.