(T-098) Population pharmacokinetic modeling of Binimetinib in Healthy Volunteers and Participants with BRAF V600-mutant or NRAS-mutant Solid Tumors

Erik Hahn, MS – Associate Director, Clinical Pharmacology, Pfizer Inc., Boulder, CO, USA; Yazdi Pithavala, PhD – Executive Director, Clinical Pharmacology, Pfizer Inc., La Jolla, CA, USA; Jennifer Hibma, PharmD – Director, Pharmacometrics, Pfizer Inc., La Jolla, CA, USA

Objectives: Binimetinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activity approved in combination with encorafenib for the treatment of patients with unresectable or metastatic melanoma and metastatic non-small cell lung cancer with select BRAF V600 mutations [1]. The primary metabolic pathway accounting for binimetinib metabolism is glucuronidation via UGT1A1 [1]. The objectives of this analysis were to describe the population pharmacokinetics (popPK) of binimetinib and evaluate potential covariates that may be important predictors of binimetinib pharmacokinetics (PK).

Methods: Data from fifteen Phase 1, 2, and 3 clinical studies involving healthy volunteers, and cancer patients (melanoma, colorectal cancer, and lung cancer) were included in the analysis. Upon selection of a base model, covariate screening was employed to identify potentially influential covariates on binimetinib PK. The first-order conditional estimation with interaction method was used in NONMEM v 7.5.0 for binimetinib popPK model development. Perl-speaks-NONMEM version 5.6.0 was used for covariate testing.

Results: A 2-compartment model with parallel but linked zero- and first-order absorption described the pooled clinical PK data well, including 10,455 concentrations from 1,457 subjects. Apparent clearance and apparent volume of distribution of central compartment for binimetinib were estimated to be 21 L/hr and 24.3 L, respectively. All model parameters were estimated with good precision (relative standard error < 25%) and were within 95% confidence intervals. Both baseline total bilirubin and age were found to be statistically significant predictors of binimetinib apparent clearance. The effect of age on binimetinib clearance was not considered clinically significant, however increases in total bilirubin, as when seen with hepatically impaired patients could lead to increases in binimetinib exposure (as observed in a study conducted in hepatically impaired participants) [1].

Conclusion: This popPK model adequately described the plasma PK of binimetinib. The results of this analysis, is in agreement with the hepatic impairment study findings and suggested adjustments in the approved product labeling [1].

Citations: 1. US Food and Drug Administration. Mektovi: Highlights of prescribing information (2018).