Abstract
Objective
Fuzuloparib is an orally administered poly [ADP-ribose] polymerase 1 (PARP1) inhibitor and has potential anti-tumor effect on ovarian cancer (such as fallopian tube cancer and primary peritoneal cancer) in China. As fuzuloparib is metabolized mainly by CYP3A4, we explored the effect of itraconazole, a strong CYP3A4 inhibitor, on a single oral dose of fuzuloparib in healthy male subjects.
Methods
An open-label, single-arm, fixed sequence study was conducted. Twenty healthy adult males received one single dose of fuzuloparib (20 mg) with one dose administered alone and the other dose coadministered with itraconazole. Subjects received 200 mg QD itraconazole for 6 days during the study. Serials of blood samples were collected pre-dose of each fuzuloparib capsule administration and 48 h post-dose, and were used to analyze the PK parameters of fuzuloparib.
Results
Coadministration of repeated 200 mg QD oral doses of itraconazole for 6 days increased fuzuloparib exposure by 1.51-fold and 4.81-fold for peak plasma concentration and area under the plasma concentration–time curve (AUC), respectively. Oral administration of 20 mg fuzuloparib alone or together with itraconazole was safe and tolerable in healthy male subjects.
Conclusion
The CYP3A4 inhibitor itraconazole has a significant influence on the PK behavior of fuzuloparib, suggesting to avoid using strong CYP3A4 inhibitors simultaneously with fuzuloparib. If it is necessary to use a strong CYP3A4 inhibitor, fuzuloparib would be discontinued and be restored to the original dose and frequency of administration after 5–7 half lives of CYP3A4 inhibitor stopped.
Trial registration
http://www.chinadrugtrials.org.cn/index.html, CTR20191271.
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Data availability
For access to the raw data associated with this study, please contact the corresponding author directly.
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Acknowledgements
The authors thank all study participants, administrative staff, and clinical study team members.
Funding
The clinical trial was sponsored by Jiangsu Hengrui Pharmaceuticals Co., Ltd., Capital Science and Technology Leading Talent Training Project (Z191100006119017), and Beijing Hospitals Authority Ascent Plan (DFL20190803).
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The study protocol, protocol amendments, and all applicable documents (including informed consent form) were reviewed and approved by the Ethics Committee of Xuanwu Hospital Capital Medical University (2019 No.018).
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Informed consent was obtained from all patients prior to screening.
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Hu, C., Zhang, Y., Pei, T. et al. Itraconazole interferes in the pharmacokinetics of fuzuloparib in healthy volunteers. Cancer Chemother Pharmacol 91, 523–529 (2023). https://doi.org/10.1007/s00280-023-04536-5
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DOI: https://doi.org/10.1007/s00280-023-04536-5