Itraconazole interferes in the pharmacokinetics of fuzuloparib in healthy volunteers.

Abstract

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. An open-label, single-arm, fixed sequence study was conducted. Twenty healthy adult males received one single dose of fuzuloparib (20mg) with one dose administered alone and the other dose coadministered with itraconazole. Subjects received 200mg QD itraconazole for 6days during the study. Serials of blood samples were collected pre-dose of each fuzuloparib capsule administration and 48h post-dose, and were used to analyze the PK parameters of fuzuloparib. Coadministration of repeated 200mg QD oral doses of itraconazole for 6days 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 20mg fuzuloparib alone or together with itraconazole was safe and tolerable in healthy male subjects. 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. http://www.chinadrugtrials.org.cn/index.html , CTR20191271.