Phase 1 study to evaluate the effects of rifampin or itraconazole on the pharmacokinetics of limertinib (ASK120067), a novel mutant-selective inhibitor of the epidermal growth factor receptor in healthy Chinese subjects

ABSTRACTBackground Limertinib is a novel mutant-selective and irreversible inhibitor of the epidermal growth factor receptor under development. A phase 1 open, two-period, single-sequence, self-controlled, two-part study was initiated to characterize the effects of a strong CYP3A4 inducer (rifampin) or inhibitor (itraconazole) on the pharmacokinetics of limertinib.Research design and methods Twenty-four healthy subjects in each part received a single dose of limertinib alone (160 mg, Part A; 80 mg, Part B) and with multiple doses of rifampin 600 mg once daily (Part A) or itraconazole 200 mg twice daily (Part B).Results Coadministration of rifampin decreased exposure (area under the plasma concentration-time curve from time 0 to infinity, AUC0-inf) of limertinib and its active metabolite CCB4580030 by 87.86% (geometric least-squares mean [GLSM] ratio, 12.14%; 90% confidence interval [CI], 9.89–14.92) and 66.82% (GLSM ratio, 33.18%; 90% CI, 27.72–39.72), respectively. Coadministration of itraconazole increased the AUC0-inf of limertinib by 289.8% (GLSM ratio, 389.8%; 90% CI, 334.07–454.82), but decreased that of CCB4580030 by 35.96% (GLSM ratio, 64.04%; 90% CI, 50.78–80.77).Conclusions Our study demonstrates that the concomitant use of limertinib with strong CYP3A inducers or inhibitors is not recommended. A single dose of limertinib, administered with or without rifampin or itraconazole, is generally safe and well tolerated in healthy Chinese subjects.Clinical trial registration www.clinicaltrials.gov identifier is NCT05631678.KEYWORDS: Limertinibdrug-drug interactionpharmacokineticsrifampinitraconazoleCYP 3A4EGFR-TKI Declaration of interestsM Lui and H Gui were former employees of Jiangsu Aosaikang Pharmaceutical Co., Ltd. (Nanjing, China). This study received funding from Jiangsu Aosaikang Pharmaceutical Co., Ltd. (Nanjing, China). The funder had the following involvement with the study including study design, data analysis and preparation of the manuscript.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 disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Data availability statementThe data that support the findings of this study are available from the corresponding author upon reasonable request.Ethics statementThe studies were conducted in accordance with the principles of the Declaration of Helsinki, the Good Clinical Practice guidelines of the International Council for Harmonisation, and any applicable national and local laws and regulations. The study protocols and informed consent documents were approved by the institutional review board (IRB) of Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School (IRB#: 2022–127). Informed consent was obtained from all individual participants included in the study.Author contributionsB Cao, H Guo and J Li designed the research. All authors participated in the research and reviewed the manuscript. B Cao, L Huang and M Liu analyzed the data. B Cao and H Guo contributed to protocol development and manuscript preparation.AcknowledgmentsThe authors would like to thank all subjects and their families. Plasma samples were analysed by Jiangsu Wanlue Pharmaceutical Technology Co., Ltd. and statistical analysis was performed by Shanghai Renzhi Data Technology Co., Ltd.Supplementary materialSupplemental data for this article can be accessed online at https://doi.org/10.1080/17425255.2023.2260738Additional informationFundingThis manuscript was funded by Jiangsu Aosaikang Pharmaceutical Co., Ltd. (Nanjing, China), and also supported partly by China National Major Project for New Drug Innovation [2017ZX09304015] and funding for Clinical Trials from Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School [2022-LCYJ-PY-19].