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

ABSTRACT

Background

Famitinib, 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).

Methods

A 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.

Results

C_max, AUC_0-t and AUC_0-∞ were raised by 40.6%, 77.7% and 81.6%, respectively, and t_1/2 was prolonged from 36.08 hours to 48.24 hours for famitinib. In contrast, C_max, AUC_0-t and AUC_0-∞ 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.

Conclusions

Single 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 registration

This trial was registered at http://www.chinadrugtrials.org.cn/index.html. (Registration number: CTR20201824.)

KEYWORDS:

• Famitinib
• itraconazole
• SHR116637
• drug interactions
• CYP3A inhibitor
• P-gp
• pharmacokinetics

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Study protocol and safety evaluation were done by J Shen. Y Huang was responsible for conducting this clinical trial. Y Jia conducted this clinical trial, providing protocol-specific training for all investigators and reviewing the manuscript. X Chen analyzed the data. C Wang was responsible for conducting this trial and wrote the manuscript. Y Wang was sub-investigator of this trial. M Wang contributed to drug administration and healthy volunteer management. P Wu was the research nurse.

Acknowledgments

The authors thank clinical staff of Yijishan Hospital for participating in the discussion of the clinical protocol and being responsible for the management of the subjects and the collection of plasma samples. We appreciate the contributions of the study sponsor, Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Ethics approval

The protocol and consent documents were approved by the Ethics Committee on Drugs, Instruments and New Technologies, Yijishan Hospital, Wannan Medical College. It was conducted in accordance with the Declaration of Helsinki, Guideline for Good Clinical Practice (GCP) released by the NMPA, in compliance with FDA regulations for informed consent and protection of subject rights as described in Investigator Responsibilities – Protecting the Rights, Safety, and Welfare of Study Subjects and related national regulations.

Patient consent statement

Written informed consent was obtained from all subjects before commencement of this study.

Clinical trial registration

Registration Number: CTR CTR20201824.

Additional information

Funding

This work was supported by Special Foundation for Talents of Yijishan Hospital (YR201913; YR202015); Funding of “Peak” Training Program for Wannan Medical College (GF2019J05; GF2019J06); Funding of “Climbing Peak” Training Program for Innovation Technology team of Yijishan Hospital, Wannan Medical College (KPF2019016).