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

Noelia Nebot, Christina S Won, Victor Moreno, Eva Muñoz-Couselo, Dung-Yang Lee, Eduard Gasal, Emmanuel Bouillaud, Noelia Nebot, Christina S Won, Victor Moreno, Eva Muñoz-Couselo, Dung-Yang Lee, Eduard Gasal, Emmanuel Bouillaud

Abstract

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 (Cmax ), an earlier time to Cmax , but only a 7% increase in area under the concentration-time curve from time 0 (predose) extrapolated to infinite time. Midazolam Cmax and AUC extrapolated to infinite time decreased by 47% and 65%, respectively, with little effect on time to Cmax . 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.

Trial registration: ClinicalTrials.gov NCT02082665.

Keywords: CYP3A4; OATP; dabrafenib; drug interaction; pharmacokinetics; transporters.

Conflict of interest statement

N.N., C.S.W., and D.‐Y.L. are former employees of Novartis and have nothing to disclose beyond their current affiliation. V.M. reports personal fees from Bristol Myers Squibb, Janssen, and Bayer, outside the submitted work. E.G. is an employee of Novartis and reports stocks in Novartis. E.B. is an employee of Novartis. E.M.‐C. declares no conflict of interest.

© 2021 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Study design. PK, pharmacokinetic.
Figure 2
Figure 2
Mean rosuvastatin concentration‐time profiles after administration of rosuvastatin alone (PK day 1), coadministration with dabrafenib at initiation of dosing (PK day 8), and after repeat‐dose administration of dabrafenib at steady state (PK day 22). PK, pharmacokinetic.
Figure 3
Figure 3
Mean midazolam concentration‐time profiles after administration of midazolam alone (PK day 1), coadministration with dabrafenib at initiation of dosing (PK day 8), and after repeat‐dose administration of dabrafenib at steady state (PK day 22). PK, pharmacokinetic.

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