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The effect of itraconazole and rifampicin on the pharmacokinetics of osimertinib
Author(s) -
Vishwanathan Karthick,
Dickinson Paul A.,
So Karen,
Thomas Karen,
Chen YuhMin,
De Castro Carpeño Javier,
Dingemans AnneMarie C.,
Kim Hye Ryun,
Kim JooHang,
Krebs Matthew G.,
ChihHsin Yang James,
Bui Khanh,
Weilert Doris,
Harvey R. Donald
Publication year - 2018
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.13534
Subject(s) - osimertinib , rifampicin , itraconazole , pharmacology , pharmacokinetics , cmax , cyp3a , cyp3a4 , medicine , discontinuation , lung cancer , epidermal growth factor receptor , erlotinib , cancer , tuberculosis , dermatology , pathology , cytochrome p450 , antifungal , metabolism
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 C max 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 C ss,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 C ss,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.