Effect of a moderate CYP3A inducer efavirenz on the pharmacokinetics of fuzuloparib: An open-label, fixed sequence study in Chinese healthy male subjects.

ABSTRACT

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).