D. Ouellet, E. Gibiansky, C. Leonowens
Jun 1, 2014
Citations
5
Influential Citations
62
Citations
Quality indicators
Journal
The Journal of Clinical Pharmacology
Abstract
Dabrafenib is a BRAF kinase inhibitor indicated for the treatment of BRAF V600E mutation‐positive melanoma. The population pharmacokinetics of dabrafenib, including changes over time and relevant covariates, were characterized based on results from four clinical studies using a nonlinear mixed effects model with a full covariate approach. Steady‐state exposures of dabrafenib metabolites (hydroxy‐, carboxy‐, and desmethyl‐dabrafenib) were characterized separately. The pharmacokinetics of dabrafenib were adequately described by non‐inducible and inducible apparent clearance that increased with dose and time. Total steady‐state clearance (CL/F) at 150 mg BID dose was 34.3 L/h. Based on the induction half‐life (67 hours), steady state should be achieved within 14 days of dosing. Capsule shell was the most significant covariate (55%) while sex and weight had only a small impact on exposure (<20%). The AUC ratio (hypromellose:gelatin capsule) is predicted to be 1.80 and 1.42 following single and repeat dosing, respectively. Age, renal (mild and moderate), and hepatic (mild) impairment were not significant covariates. Steady‐state pre‐dose concentration (%CV) of dabrafenib and of hydroxy‐, carboxy‐, and desmethyl‐dabrafenib at 150 mg BID were 46.6 ng/mL (83.5%), 69.3 ng/mL (64.1%), 3608 ng/mL (14.7%), and 291 ng/mL (17.2%), respectively. Capsule shell, concomitant medications, older age, and weight were predictors of metabolite exposure.