title: Population pharmacokinetics of dabrafenib, a BRAF inhibitor: effect of dose, time, covariates, and relationship with its metabolites.
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.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Daniele
authors.initials: D
authors.lastname: Ouellet
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Gibiansky
authors.forename: Cathrine
authors.initials: C
authors.lastname: Leonowens
authors.forename: Anne
authors.initials: A
authors.lastname: O'Hagan
authors.forename: Patricia
authors.initials: P
authors.lastname: Haney
authors.forename: Julie
authors.initials: J
authors.lastname: Switzky
authors.forename: Vicki L
authors.initials: VL
authors.lastname: Goodman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005780:Gelatin / Q000737:chemistry; D006801:Humans; D065347:Hypromellose Derivatives / Q000737:chemistry; D007093:Imidazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010091:Oximes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D065347:Hypromellose Derivatives; D005780:Gelatin; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib
keywords: NONMEM; dabrafenib; induction; metabolites; pharmacokinetics