The effect of itraconazole and rifampicin on the pharmacokinetics of osimertinib

Aims We investigated the effects of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampicin) on the pharmacokinetics of the epidermal growth factor receptor‐tyrosine kinase inhibitor osimertinib, in patients with advanced non‐small cell lung cancer in two Phase I, open‐label, two‐part clinical studies. Part one of both studies is reported. Methods In the itraconazole study (NCT02157883), patients received single‐dose osimertinib 80 mg on Days 1 and 10 and itraconazole (200 mg twice daily) on Days 6–18 orally. In the rifampicin study (NCT02197247), patients received osimertinib 80 mg once daily on Days 1–77 and rifampicin 600 mg once daily on Days 29–49. Results In the itraconazole study (n = 36), the geometric least squares mean (GMLSM) ratios (osimertinib plus itraconazole/osimertinib alone) for Cmax and AUC were 80% (90% CI 73, 87) and 124% (90% CI 115, 135), respectively, below the predefined no‐effect upper limit of 200%. In the rifampicin study (n = 40), the GMLSM ratios (osimertinib plus rifampicin/osimertinib alone) for Css,max and AUCτ were 27% (90% CI 24, 30) and 22% (90% CI 20, 24), respectively, below the predefined no‐effect lower limit of 50%. The induction effect of rifampicin was apparent within 7 days of initiation; osimertinib Css,max and AUCτ values returned to pre‐rifampicin levels within 3 weeks of rifampicin discontinuation. No new osimertinib safety findings were observed. Conclusions Osimertinib can be co‐administered with CYP3A4 inhibitors, but strong CYP3A inducers should be avoided if possible.