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

Aim Methods We 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. Fifty-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. Results Conclusions Geometric 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 C-max of 77% (63, 94) which was not contained within the limits. GLSM ratios of rosuvastatin plus osimertinib for AUC were 135% (115-157) and C-max were 172 (146, 203): outside the no relevant effect limits. Osimertinib 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.