CYP3A inhibitor itraconazole affect pharmacokinetic behavior of famitinib and its active metabolite: results of a single-center, single-arm, open-label and fixed sequence study

BackgroundFamitinib, the novel oral multitargeting tyrosine kinase inhibitor, was developed for treatment of patients with advanced solid cancer. This investigation assessed the pharmacokinetic (PK) effects of itraconazole, an officially recommended CYP3A4 strong inhibitor, on famitinib and its metabolite (SHR116637).MethodsA single-center, single-arm, open-label, and fixed sequence study was conducted in 22 healthy subjects. Famitinib was administered as a single oral 15 mg on Day1. Itraconazole 200 mg once daily was given from Day12 to Day24, concomitantly with famitinib on Day15 and for follow-up during Day30 to Day32. Blood sampling followed each famitinib dosage for PK analysis of famitinib and SHR116637. Safety and tolerability were also assessed throughout the treatment.ResultsCmax, AUC0-t and AUC0-infinity were raised by 40.6%, 77.7% and 81.6%, respectively, and t1/2 was prolonged from 36.08 hours to 48.24 hours for famitinib. In contrast, Cmax, AUC0-t and AUC0-infinity were reduced by 63.5%, 42.6%, and 39.0%, respectively, for SHR116637. Eight (36.4%) subjects reported seventeen treatments that emerged adverse events (all grade 1-2 in severity) all recovered at follow-up period.ConclusionsSingle oral dose of 15 mg famitinib and co-therapy with 200 mg intraconazole were safe and well tolerated in healthy subjects. Famitinib should be avoided in conjunction with strong CYP3A inhibitors if possible.Trial registrationThis trial was registered at http://www.chinadrugtrials.org.cn/index.html. (Registration number: CTR20201824.)