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.

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

“…It was observed that plasma AUC0‐12 h (day 21) of dabrafenib at repeat dosing was lower than that at AUC0‐inf (day 1), which may support the result that dabrafenib induces self‐induction of metabolism. The results observed in this study are consistent with the results that have been observed in global studies 28. Similarly rapid absorption of trametinib was also noticed following repeated dosing of trametinib 2 mg q.d.…”

Therapeutic drug monitoring of small molecule kinase inhibitors in oncology in a real‐world cohort study: does age matter?

“…The proportion of patients reaching their predefined efficacy target was comparable between both age groups, with 68% of elderly patients and 61% of younger patients reaching the target ( P = 0.17), as shown in Table . Although no clinically relevant target concentration has been established for dabrafenib, a pooled population PK analysis of four clinical trials reported a typical pre‐dose concentration of 46.6 ng ml −1 . This plasma concentration was reached by 94% of older patients and 74% of younger patients, not reaching significance ( P = 0.11).…”

Clinical Drug–Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib

“…As both alectinib and M4 inhibit ALK with similar potency in vitro and exhibit similar plasma protein binding, it is believed that both alectinib and M4 contribute to overall alectinib efficacy and safety, and thus the effect of posaconazole on the combined exposure of alectinib and M4, adjusted for molecular weight, was determined. This approach has been applied to interpretation of clinical data for other tyrosine kinase inhibitors with active metabolites (eg, regorafenib, dabrafenib, and sunitinib) . Coadministration with posaconazole only had a minor effect on the combined exposure of alectinib and M4, with a geometric mean ratio for AUC 0–∞ of 136%.…”