Summary
Purpose
Pyrotinib (PTN), an irreversible EGFR/HER2 dual tyrosine kinase inhibitor used for treating HER2-positive breast cancer, is primarily metabolized by cytochrome P450 (CYP)3A4 isozyme. Rifampicin (RIF) is a strong index CYP3A4 inducer. Therefore, the study aimed to elucidate the effect of RIF on PTN pharmacokinetics (PK) in Chinese healthy volunteers.
Methods
This phase I, open-label study investigated the effects of steady-state RIF administration on single-dose PK of PTN. 18 healthy participants were enrolled in this trial, who received a single oral dose of 400 mg of PTN on days 1 and 13, and were administrated with RIF 600 mg qd on days 6 through 16. RIF was administrated on an empty stomach, PTN were administrated orally in the morning 30 min after the start of the standard meal. Serial PK samples for PTN were collected on days 1 and days 13. Safety assessments were performed via clinical laboratory tests throughout the study.
Results
18 subjects were enrolled and 16 completed the study. RIF significantly reduced PTN exposure: Geometric least-squares mean ratios (90% CI) for PTN + RIF versus PTN alone were 0.04 (0.034,0.049), 0.04 (0.037,0.054), and 0.11 (0.09,0.124) for area under the curve from time zero to time of last quantifiable concentration (AUC0 − t), area under the curve from time zero to infinity (AUC0−∞ ), and maximum observed plasma concentration(Cmax), respectively. PTN alone and co-administered with RIF was well tolerated.
Conclusion
The exposure of PTN was significantly affected by the action of RIF. The findings suggest that concomitant strong CYP3A4 inducers should be avoided during PTN treatment. Concurrent administration of PTN and RIF was well tolerated.
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All data generated or analysed during this study are included in this published article.
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Acknowledgements
We would like to thank all the subjects who participated in this study, study coordinator, the clinical investigators and support staff.
Funding
This study was supported by scientific research project of Jiangsu Medical Products Administration (202106).
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Designed Research: Wei Qian, Hui-ping wang. Performed Research : Ming-min Cai, Ting Dou, Lu Tang, Qiu-yue Sun. Analyzed Data: Ming-min Cai, Zi-hong Zhai. Wrote Manuscript: Ming-min Cai, Wei Qian. Language Modification:Ming-min Cai, Wei Qian.
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All procedures performed in the study involving human participants were conducted in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
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The phase I clinical trial was approved by Ethics Committee.
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Cai, Mm., Dou, T., Tang, L. et al. Effects of rifampicin on antineoplastic drug pyrotinib maleate pharmacokinetics in healthy subjects. Invest New Drugs 40, 756–761 (2022). https://doi.org/10.1007/s10637-022-01241-7
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DOI: https://doi.org/10.1007/s10637-022-01241-7