Population pharmacokinetics of dabrafenib, a BRAF inhibitor: effect of dose, time, covariates, and relationship with its metabolites

J Clin Pharmacol. 2014 Jun;54(6):696-706. doi: 10.1002/jcph.263. Epub 2014 Jan 17.


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.

Trial registration: ClinicalTrials.gov NCT00880321 NCT01153763 NCT01227889 NCT01266967.

Keywords: NONMEM; dabrafenib; induction; metabolites; pharmacokinetics.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Gelatin / chemistry
  • Humans
  • Hypromellose Derivatives / chemistry
  • Imidazoles / administration & dosage
  • Imidazoles / blood
  • Imidazoles / pharmacokinetics*
  • Male
  • Middle Aged
  • Models, Biological*
  • Oximes / administration & dosage
  • Oximes / blood
  • Oximes / pharmacokinetics*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / blood
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Young Adult


  • Antineoplastic Agents
  • Imidazoles
  • Oximes
  • Protein Kinase Inhibitors
  • Hypromellose Derivatives
  • Gelatin
  • Proto-Oncogene Proteins B-raf
  • dabrafenib

Associated data

  • ClinicalTrials.gov/NCT00880321
  • ClinicalTrials.gov/NCT01153763
  • ClinicalTrials.gov/NCT01227889
  • ClinicalTrials.gov/NCT01266967