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Dabrafenib is an oral BRAF kinase inhibitor approved for the treatment of various  BRAF  V600 mutation–positive solid tumors. In vitro observations suggesting cytochrome P450 (CYP) 3A induction and organic anion transporting polypeptide (OATP) inhibition prompted us to evaluate the effect of dabrafenib 150 mg twice daily on the pharmacokinetics of midazolam 3 mg (CYP3A substrate) and rosuvastatin 10 mg (OATP1B1/1B3 substrate) in a clinical phase 1, open‐label, fixed‐sequence study in patients with  BRAF  V600 mutation–positive tumors. Repeat dabrafenib dosing resulted in a 2.56‐fold increase in rosuvastatin maximum observed concentration (C max ), an earlier time to C max , but only a 7% increase in area under the concentration‐time curve from time 0 (predose) extrapolated to infinite time. Midazolam C max  and AUC extrapolated to infinite time decreased by 47% and 65%, respectively, with little effect on time to C max . No new safety findings were reported. Exposure of drugs that are CYP3A4 substrates is likely to decrease when coadministered with dabrafenib. Concentrations of medicinal products that are sensitive OATP1B1/1B3 substrates may increase during the absorption phase.

clinical pharmacology in drug development

Evaluation of the Effects of Repeat‐Dose Dabrafenib on the Single‐Dose Pharmacokinetics of Rosuvastatin (OATP1B1/1B3 Substrate) and Midazolam (CYP3A4 Substrate)