2026-04-17T16:01:22Zhttps://recercat.cat/oai/request

oai:recercat.cat:11351/77662024-06-06T08:42:19Zcom_2072_378070com_2072_378040col_2072_378092

Evaluation of the Effects of Repeat-Dose Dabrafenib on the Single-Dose Pharmacokinetics of Rosuvastatin (OATP1B1/1B3 Substrate) and Midazolam (CYP3A4 Substrate) Nebot, Noelia Won, Christina S. Lee, Dung-Yang Gasal, Eduard Bouillaud, Emmanuel Muñoz Couselo, Eva Moreno, Victor Institut Català de la Salut [Nebot N, Lee DY, Gasal E] 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] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Bouillaud E] Novartis Pharma AG, Basel, Switzerland Vall d'Hebron Barcelona Hospital Campus Farmacocinètica Proteïnes quinases - Inhibidors Medicaments - Interacció PHENOMENA AND PROCESSES::Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Interactions CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors Other subheadings::Other subheadings::/pharmacology PHENOMENA AND PROCESSES::Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacokinetics FENÓMENOS Y PROCESOS::fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::interacciones farmacológicas COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas Otros calificadores::Otros calificadores::/farmacología FENÓMENOS Y PROCESOS::fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::farmacocinética Dabrafenib; Drug interaction; Pharmacokinetics Dabrafenib; Interacción de fármacos; Farmacocinética Dabrafenib; Interacció de fàrmacs; Farmacocinètica 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. This study was sponsored by GlaxoSmithKline; dabrafenib and trametinib are assets of Novartis AG as of March 2, 2015. 2022-06-30T06:48:51Z 2022-06-30T06:48:51Z 2021-09 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Nebot N, Won CS, Moreno V, Muñoz‐Couselo E, Lee DY, Gasal E, et al. Evaluation of the Effects of Repeat‐Dose Dabrafenib on the Single‐Dose Pharmacokinetics of Rosuvastatin (OATP1B1/1B3 Substrate) and Midazolam (CYP3A4 Substrate). Clin Pharmacol Drug Dev. 2021 Sep;10(9):1054–63. 2160-7648 https://hdl.handle.net/11351/7766 10.1002/cpdd.937 33932130 000645938100001 eng Clinical Pharmacology in Drug Development;10(9) https://doi.org/10.1002/cpdd.937 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess application/pdf Wiley Scientia