Introduction. The combination of a BRAF inhibitor, dabrafenib and a MEK inhibitor, trametinib (CombiDT) has improved survival outcomes compared with chemotherapy or BRAF inhibitor monotherapy in advanced BRAF V600E/K melanoma. However, the use of CombiDT has a high incidence of pyrexia, causing treatment delays (Menzies, 2015). The pharmacokinetics and metabolism of dabrafenib and trametinib may give clues relating to the incidence side effects such as pyrexia.
Aims. To investigate the pharmacokinetics of dabrafenib and to determine if and to what extent the exposure to the drug and metabolites contribute to the incidence of pyrexia.
Methods. Patients treated with CombiDT were recruited onto Neo-Adjuvant Combi Trial (protocol ID: 200332). Plasma samples were analysed for drug and metabolite concentrations using LC-MS. Vemurafenib was used as an internal standard. A population pharmacokinetic model using NONMEM was applied to dabrafenib data to derive AUC and Cmin values for each patient.
Results. Dabrafenib (4.0-4628ng/ml) and trametinib (1.0-45ng/ml) concentrations were measurable in 151 samples from 34 patients. Three dabrafenib metabolites (carboxy-, hydroxy- and N-desmethyl-dabrafenib) were also measurable and showed a high degree of inter-patient variation. A 2-compartment model with first-order absorption provided the best fit to the dabrafenib data. The incidence of pyrexia or treatment interruption was not associated with lower average AUC or Cmin nor was there any apparent association with average concentration of dabrafenib metabolites.
Discussion. An analytical method was successfully established to measure dabrafenib, trametinib and metabolite concentrations. Pharmacokinetics of dabrafenib was characterised by NONMEM with ongoing investigation of the effects of covariates (age, gender, weight, height, creatinine etc.), dose interruptions or concomitant medications such as corticosteroids (used for management of pyrexia). Exploration of the potential relationships between the exposure to dabrafenib, trametinib or metabolites and the incidence of pyrexia is ongoing.
Menzies AM et al (2014) Annals of Oncology 26: 415–421.