The effect of itraconazole and rifampicin on the pharmacokinetics of osimertinib

Abstract

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.

Keywords: clinical pharmacology, drug metabolism; drug analysis, lung cancer; drug information; drug interactions; oncology; pharmacokinetics, biomarkers.

© 2018 The British Pharmacological Society.

Figures

Figure 1

Study design. EGFR, epidermal growth factor receptor; EGFRm, epidermal growth factor receptor‐tyrosine kinase inhibitor sensitizing; NCSLC, non‐small cell lung cancer; TKI, tyrosine kinase inhibitor

Figure 2

A. Plasma concentration of osimertinib versus time by treatment in the itraconazole study (data are geometric mean ± Geo SD, semi‐log scale, PK analysis set). Osimertinib: Osimertinib 80 mg single oral dose on Day 1. Period ends when patient receives first itraconazole dose. Osimertinib + itraconazole: itraconazole 200 mg bd Days 6–18 and osimertinib 80 mg single oral dose on Day 10. Period starts when patient receives first itraconazole dose. B. Plasma concentration of osimertinib versus time by treatment in the rifampicin study (data are geometric mean ± Geo SD, semi‐log scale, PK analysis set). Osimertinib: Osimertinib 80 mg single oral dose on Day 1. Period ends when patient receives first itraconazole dose. Osimertinib + itraconazole: itraconazole 200 mg bd Days 6–18 and osimertinib 80 mg single oral dose on Day 10. Period starts when patient receives first itraconazole dose. C. Plasma trough concentration (nM) of osimertinib versus study day [data are geometric mean (±Geo SD), PK analysis set]. Osimertinib (1): Osimertinib 80 mg single oral dose on Days 1–28. Period ends when patient receives first rifampicin dose. Osimertinib + rifampicin (2): Osimertinib 80 mg single oral dose and rifampicin 600 mg daily on Days 29–49. Period starts when subject receives first rifampicin dose and ends when patient first receives osimertinib dose on a day after the date of last dose of rifampicin. Osimertinib (3): Osimertinib 80 mg single oral dose on Days 50–77. Period starts when patient first receives osimertinib dose on a day after the date of last dose of rifampicin, and ends at completion of/withdrawal from Part A or first dose of osimertinib in Part B. Geo, geometric; PK, pharmacokinetic; SD, standard deviation