Dabrafenib is a potent and selective inhibitor of BRAF-mutant kinase that is approved, as monotherapy or in combination with trametinib (mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor), for unresectable or metastatic BRAF-mutated melanoma, advanced non-small cell lung cancer and anaplastic thyroid cancer harbouring the BRAF mutation. The recommended dose of dabrafenib is 150 mg twice daily (bid) under fasted conditions. After single oral administration of the recommended dose, the absolute oral bioavailability (F) of dabrafenib is 95%. Dabrafenib shows a time-dependent increase in apparent clearance (CL/F) following multiple doses, which is likely due to induction of its own metabolism through cytochrome P450 (CYP) 3A4. Therefore, steady state is reached only after 14 days of daily dose administration. Moreover, the extent of this auto-induction process is dependent on the dose, which explains why dabrafenib systemic exposure at steady state increases less than dose proportionally over the dose range of 75-300 mg bid. The main elimination route of dabrafenib is the oxidative metabolism via CYP3A4/2C8 and biliary excretion. Among the three major metabolites identified, hydroxy-dabrafenib appears to contribute to the pharmacological activity. Age, sex and body weight did not have any clinically significant influence on plasma exposure to dabrafenib. No dose adjustment is needed for patients with mild renal or hepatic impairment, whereas the impacts of severe impairment on dabrafenib pharmacokinetics remain unknown. Considering that dabrafenib is a substrate of CYP3A4/2C8 and is a CYP3A4/2B6/2C inducer, drug-drug interactions are expected with dabrafenib. The relationship between clinical outcomes and plasma exposure to dabrafenib and hydroxy-dabrafenib should be investigated more deeply.

Variations in clinical response to tamoxifen (TAM) may be related to polymorphic cytochromes P450 (CYPs) involved in forming its active metabolite endoxifen (ENDO). We developed a population pharmacokinetic (PopPK) model for tamoxifen and six metabolites to determine clinically relevant factors of ENDO exposure. Concentration‐time data for TAM and 6 metabolites come from a prospective, multicenter, 3‐year follow‐up study of adjuvant TAM (20 mg/day) in patients with breast cancer, with plasma samples drawn every 6 months, and genotypes for 63 genetic polymorphisms (PHACS study, NCT01127295). Concentration data for TAM and 6 metabolites from 928 patients (n = 27,433 concentrations) were analyzed simultaneously with a 7‐compartment PopPK model. CYP2D6 phenotype (poor metabolizer (PM), intermediate metabolizer (IM), normal metabolizer (NM), and ultra‐rapid metabolizer (UM)), CYP3A4*22, CYP2C19*2, and CYP2B6*6 genotypes, concomitant CYP2D6 inhibitors, age, and body weight had a significant impact on TAM metabolism. Formation of ENDO from N‐desmethyltamoxifen was decreased by 84% (relative standard error (RSE) = 14%) in PM patients and by 47% (RSE = 9%) in IM patients and increased in UM patients by 27% (RSE = 12%) compared with NM patients. Dose‐adjustment simulations support an increase from 20 mg/day to 40 and 80 mg/day in IM patients and PM patients, respectively, to reach ENDO levels similar to those in NM patients. However, when considering Antiestrogenic Activity Score (AAS), a dose increase to 60 mg/day in PM patients seems sufficient. This PopPK model can be used as a tool to predict ENDO levels or AAS according to the patient’s CYP2D6 phenotype for TAM dose adaptation.