TY - JOUR
T1 - The effect of itraconazole and rifampicin on the pharmacokinetics of osimertinib
AU - Vishwanathan, Karthick
AU - Dickinson, Paul A
AU - So, Karen
AU - Thomas, Karen
AU - Chen, Yuh-Min
AU - De Castro Carpeño, Javier
AU - Dingemans, Anne-Marie C
AU - Kim, Hye Ryun
AU - Kim, Joo-Hang
AU - Krebs, Matthew G
AU - Yang, James Chih-Hsin
AU - Bui, Khanh
AU - Weilert, Doris
AU - Harvey, R Donald
N1 - This article is protected by copyright. All rights reserved.
PY - 2018/1/30
Y1 - 2018/1/30
N2 - AIMS: We investigated the effects of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampicin) on the pharmacokinetics of the epidermal growth factor receptor 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 AUCT 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 AUCT 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.
AB - AIMS: We investigated the effects of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampicin) on the pharmacokinetics of the epidermal growth factor receptor 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 AUCT 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 AUCT 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.
KW - Journal Article
U2 - 10.1111/bcp.13534
DO - 10.1111/bcp.13534
M3 - Article
C2 - 29381826
SN - 0306-5251
JO - British Journal of Clinical Pharmacology
JF - British Journal of Clinical Pharmacology
ER -
