Effect of multiple-dose osimertinib on the pharmacokinetics of simvastatin and rosuvastatin

Abstract : AimWe report on two Phase 1, open‐label, single‐arm studies assessing the effect of osimertinib on simvastatin (CYP3A substrate) and rosuvastatin (breast cancer resistance protein substrate [BCRP] substrate) exposure in patients with advanced epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung cancer who have progressed after treatment with an EGFR tyrosine kinase inhibitor, to determine, upon coadministration, whether osimertinib could affect the exposure of these agents.MethodsFifty‐two patients in the CYP3A study (pharmacokinetic [PK] analysis, n = 49), and 44 patients in the BCRP study were dosed (PK analysis, n = 44). In the CYP3A study, patients received single doses of simvastatin 40 mg on Days 1 and 31, and osimertinib 80 mg once daily on Days 3–32. In the BCRP study, single doses of rosuvastatin 20 mg were given on Days 1 and 32, and osimertinib 80 mg once daily on Days 4–34.ResultsGeometric least squares mean (GLSM) ratios (90% confidence intervals) of simvastatin plus osimertinib for area under the plasma concentration–time curves from zero to infinity (AUC) were 91% (77–108): entirely contained within the predefined no relevant effect limits, and Cmax of 77% (63, 94) which was not contained within the limits. GLSM ratios of rosuvastatin plus osimertinib for AUC were 135% (115–157) and Cmax were 172 (146, 203): outside the no relevant effect limits.ConclusionsOsimertinib is unlikely to have any clinically relevant interaction with CYP3A substrates and has a weak inhibitory effect on BCRP. No new safety concerns were identified in either study.
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01924733
Contributeur : Lnc - Université de Bourgogne <>
Soumis le : vendredi 16 novembre 2018 - 11:24:05
Dernière modification le : mercredi 31 juillet 2019 - 15:14:03

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R Donald Harvey, Noemi Aransay, Nicolas Isambert, Jong-Seok So, Tobias Arkenau, et al.. Effect of multiple-dose osimertinib on the pharmacokinetics of simvastatin and rosuvastatin. British Journal of Clinical Pharmacology, Wiley, 2018, 84 (12), pp.2877-2888. ⟨10.1111/bcp.13753⟩. ⟨hal-01924733⟩

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