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

Autor: Nebot N; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA., Won CS; Novartis Institutes for BioMedical Research, East Hanover, New Jersey, USA., Moreno V; START Madrid-FJD, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain., Muñoz-Couselo E; VHIO - Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain., Lee DY; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA., Gasal E; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA., Bouillaud E; Novartis Pharma AG, Basel, Switzerland.
Jazyk: angličtina
Zdroj: Clinical pharmacology in drug development [Clin Pharmacol Drug Dev] 2021 Sep; Vol. 10 (9), pp. 1054-1063. Date of Electronic Publication: 2021 May 01.
DOI: 10.1002/cpdd.937
Abstrakt: 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.
(© 2021 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
Databáze: MEDLINE
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