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.