Journal Article

Effect of CYP3A4 inhibitor and induction on the pharmacokinetics and safety of FHND9041, a novel EGFR T790M inhibitor, in healthy Chinese

Lu, Chang, Zhu, Yongqiang, Chen, Rongzhen, Cheng, Dongmei, Zhou, Huan, Xie, Yunqiu, Gong, Jian, Shang, Minghong

2025

Overview

Background Non-small cell carcinoma is the main pathologic type of lung cancer, and a large number of clinical trials have shown that epidermal growth factor receptor tyrosinase inhibitors exhibit superior clinical efficacy and lower toxicity compared with chemotherapy. FHND9041 is a new irreversible EGFR T790M mutation-selective small molecule kinase inhibitor, a third-generation EGFR inhibitor developed by Nanjing Chuangte Pharmaceutical Technology Co., Ltd. The aim of this study was to evaluate the effects of oral Itraconazole capsules and oral Rifampicin capsules on the pharmacokinetic profile and safety and tolerability of a single oral dose of FHND9041 capsules in healthy Chinese male subjects. Patients and methods This study employed a single-center, open-label, fixed-sequence design, comprising two parallel groups: Group 1 received FHND9041 40 mg in combination with Itraconazole, while Group 2 received Rifampicin in combination with FHND9041 80 mg. Each group enrolled 16 subjects for a two-period study, with the first period involving monotherapy and the second period involving co-administration. All subjects participating in this clinical trial were healthy adult Chinese males. Results In healthy subjects, after a single oral administration of 40 mg FHND9041 capsules, the corrected geometric mean ratios (90% confidence intervals) of FHND9041 C max , AUC 0 − last , and AUC 0 − inf when co-administered with itraconazole capsules compared to the monotherapy phase were 111.46% (103.26 − 120.30%), 169.53% (156.21 − 183.99%), and 168.25% (156.26 − 181.15%), respectively. The 90% confidence interval for C max fell within the 80-125% range, while the 90% confidence intervals for both AUC 0 − last and AUC 0 − inf exceeded the 80-125% range. Following a single oral dose of 80 mg FHND9041 capsules, the adjusted geometric mean ratios (90% confidence intervals) of C max , AUC 0 − last , and AUC 0 − inf for FHND9041 during co-administration with Rifampicin compared to monotherapy were 52.12% (41.95 − 64.74%), 16.47% (13.34 − 20.31%), and 16.51% (13.56 − 20.09%), respectively. The 90% confidence intervals for C max , AUC 0 − last , and AUC 0 − inf all fell outside the 80 − 125% range. No serious adverse events occurred during the trial. Conclusions Co-administration with Rifampicin significantly reduced the exposure of FHND9041. Therefore, it is recommended to avoid co-administration of FHND9041 with Rifampicin and other potent CYP3A4 inducers. Conversely, co-administration with Itraconazole significantly increased the total exposure of FHND9041. Caution is advised when FHND9041 is co-administered with Itraconazole or other strong CYP3A4 inhibitors. Close monitoring of tolerability during co-administration is essential, and dose reduction may be necessary if required. FHND9041 capsules demonstrated good safety and tolerability when used alone or in combination with strong CYP3A4 inhibitors or inducers. Trial registration Registered 03/27/2023 ( http://www.chinadrugtrials.org.cn/index.html , CTR202300931).

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Administration, Oral / Adult / Alcohol / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer therapies / Chemotherapy / Clinical medicine / Clinical trials / Cytochrome P-450 CYP3A - metabolism / Cytochrome P-450 CYP3A Inducers - administration & dosage / Cytochrome P-450 CYP3A Inducers - adverse effects / Cytochrome P-450 CYP3A Inducers - pharmacology / Cytochrome P-450 CYP3A Inhibitors - administration & dosage / Cytochrome P-450 CYP3A Inhibitors - pharmacology / Drug abuse / Drug dosages / Drug Interactions / East Asian People / Enzymes / Epidermal growth factor / Epidermal growth factor receptors / ErbB Receptors - antagonists & inhibitors / ErbB Receptors - genetics / FHND9041 / Growth factors / Healthy Volunteers / Humans / Inhibitors / Itraconazole / Itraconazole - administration & dosage / Itraconazole - adverse effects / Itraconazole - pharmacology / Kinases / Lung cancer / Male / Metabolism / Metabolites / Molecules / Mutation / Non-small cell lung cancer / Oral administration / Pharmacokinetics / Pharmacology/Toxicology / Prescription drugs / Protein Kinase Inhibitors - administration & dosage / Protein Kinase Inhibitors - adverse effects / Protein Kinase Inhibitors - pharmacokinetics / Rifampin / Rifampin - administration & dosage / Rifampin - adverse effects / Rifampin - pharmacology / Safety / Safety assessment / Surgery / Toxicity / Tyrosinase / Young Adult