Population pharmacokinetics of encorafenib and binimetinib in real-world patients with BRAFV600E/K-mutant metastatic melanoma.

Abstract

PURPOSE: Encorafenib and binimetinib pharmacokinetic (PK) studies in real-world cancer patients remain scarce. We aimed to characterize their population pharmacokinetics (popPK) in routine clinical care and compare real-life exposure metrics with clinical trials data. METHODS: We conducted population pharmacokinetic (popPK) analyses in real-world patients with BRAFV600E/K-mutant metastatic melanoma to characterize interindividual variability (IIV) and identify significant covariates in MonolixSuite™. Final model-based Bayesian individual PK metrics (i.e., trough concentration, Cmin, maximal concentration, Cmax, unbound average concentration, Caverage, and area under the curve, AUCτ) were compared with data from clinical trials and potency-anchored metrics (reported half-maximal inhibitory concentration, IC50). RESULTS: Data from 66 encorafenib and 69 binimetinib patients (310 and 311 samples) were analyzed. For both drugs, a two-compartment model with first-order absorption and linear elimination best described the data. None of the studied covariates were significantly associated with model parameters. Model-predicted PK metrics (geometric mean and CV(%)) for encorafenib and binimetinib at 450 mg QD and 45 mg BID were: Cmin 19 ng/mL (73%) and 55 ng/mL (56%), Cmax 3378 ng/mL (30%) and 367 ng/mL (24%), and half-lives 12.5 h (95%) and 7.3 h (67%), respectively. Encorafenib AUC24h was 15,785 ng·h/mL (17%) and binimetinib AUC12h was 2003 ng·h/mL (22%). Monte Carlo simulation showed that reducing encorafenib from 450 mg to 300 mg once daily lowered unbound Caverage by 33% while maintaining substantial coverage relative to IC50. CONCLUSION: Overall, these metrics are comparable to those reported in clinical trial data. This population PK model could be useful to explore the exposure-response relationship in future PK/PD studies.