Summary
To evaluate the potential drug-drug interaction (DDI), safety and tolerability of fuzuloparib co-administered with a moderate CYP3A inducer efavirenz in healthy male subjects. Eighteen healthy male subjects were enrolled in a single-center, single-arm, open-label, fixed-sequence study. Fuzuloparib was administered as a single oral 50 mg under a fasting state on day 1, efavirenz (600 mg once daily) was given on days 4–17 before bed time, concomitantly with fuzuloparib on day 18, and for the follow-up 3 additional days (days 19–20). Pharmacokinetic sampling was performed following each fuzuloparib dose. Safety and tolerability were assessed during the whole process via clinical laboratory tests. Ratios of least-squares means (GMRs) and 90% geometric confidence interval (90% CI) of maximum plasma concentration (Cmax), the area under the curve of plasma concentration-time from zero to the last measurable concentration (AUC0 − t) and the area under the curve of blood concentration from zero to infinity (AUC0−∞) for fuzuloparib combined with efavirenz to fuzuloparib alone were 0.473 (0.394, 0.568), 0.220 (0.185, 0.263) and 0.221 (0.185, 0.263), respectively. Co-administration with efavirenz led to 53% and 78% decreases in fuzuloparib Cmax and AUC0−∞. All 18 subjects enrolled in this study were included in the safety analysis set. A total of 16 subjects had 62 AEs during the study period. No serious adverse events (SAE) were reported. Most treatment-emergent adverse events were grade 1 or 2 based on CTCAE. Only one grade 3 adverse event was observed. Concomitant intake of fuzuloparib with the moderate CYP3A inhibitor efavirenz resulted in a decrease in fuzuloparib AUC0−∞ and Cmax of 78% and 53% respectively. The results suggested that concomitant moderate CYP3A inducers should be avoided during the administration of fuzuloparib, or else the dosage adjustments should be required. (This trial was registered at http://www.chinadrugtrials.org.cn. The registration No. is CTR20211022, and the date of registration is 2021-05-13).
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Acknowledgements
This work was supported by Jiangsu Hengrui Co. Ltd. The authors thank all the patients who participated in this study and their families, as well as all the investigators and site staff who made the study possible.
Funding
This project was also supported by the National Natural Science Foundation of China (No. 81503340), and the National Natural Science Foundation of Jiangsu Province (No. BK20150645), Jiangsu Research Hospital Association for Precision medication (No. JY202035), and the CHIA TAI TIAQING Pharmaceutical Foundation of Jiangsu Pharmaceutical Association (No. Q202203). We thank staff involved.
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Huiping Wang and Linlin Hu contributed to the study conception and design. Material preparation, data collection and analysis were performed by Linlin Hu, Ting Dou, Qiu yue Sun, Lu Tang, Ming-min Cai and Wei Qian. The first draft of the manuscript was written by Linlin Hu and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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This study was performed in line with the principles of the Declaration of Helsinki. The study protocol was approved (approval number, 2021ZDSYLL079-P01) by the Ethics Committee of the Zhongda Hospital, Medical School, Southeast University (Nanjing, China).
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Hu, L., Dou, T., Sun, Q. et al. Effect of a moderate CYP3A inducer efavirenz on the pharmacokinetics of fuzuloparib: An open-label, fixed sequence study in Chinese healthy male subjects. Invest New Drugs 41, 276–283 (2023). https://doi.org/10.1007/s10637-023-01331-0
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DOI: https://doi.org/10.1007/s10637-023-01331-0