Pharmacokinetics, metabolism, excretion and safety of iruplinalkib (WX-0593), a novel ALK inhibitor, in healthy subjects: a phase I human radiolabeled mass balance study

ABSTRACT

Background

Iruplinalkib is a novel anaplastic lymphoma kinase (ALK) inhibitor for the treatment of ALK-positive crizotinib-resistant NSCLC.

Research design and methods

A single oral dose of 120 mg/3.7 MBq [¹⁴C]iruplinalkib was administered to healthy subjects. Blood, urine and fecal samples were collected and analyzed for iruplinalkib and its metabolites. The safety of iruplinalkib was also assessed.

Results

Iruplinalkib was absorbed quickly and eliminated slowly from plasma, with a T_max of 1.5 h and t_1/2 of 28.6 h. About 88.85% of iruplinalkib was excreted at 312 h, including 20.23% in urine and 68.63% in feces. Seventeen metabolites of iruplinalkib were identified, and M3b (demethylation), M7 (cysteine conjugation), M11 (oxidative dehydrogenation and cysteine conjugation of M3b) and M12 (oxidative dehydrogenation and cysteine conjugation) were considered the prominent metabolites in humans. Iruplinalkib-related compounds were found to be covalently bound to proteins, accounting for 7.70% in plasma and 17.96% in feces, which suggested chemically reactive metabolites were formed. There were no serious adverse events observed in the study.

Conclusions

Iruplinalkib was widely metabolized and excreted mainly through feces in humans. Unchanged iruplinalkib, cysteine conjugates and covalent protein binding products were the main drug-related compounds in circulation. Iruplinalkib was well tolerated at the study dose.

Trial registration

The trial is registered at ClinicalTrials.gov (Identifier: Anonymized).

KEYWORDS:

• ALK inhibitors
• covalent protein binding
• iruplinalkib
• mass balance
• metabolite profiling
• NSCLC

Declaration of interest

M. Ge, H Li and S. Zheng are employees of Qilu Pharmaceutical Co., Ltd. All the other authors declare no conflicts of interest. The authors have no other 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 apart from those disclosed.

Author contributions

L. Miao and H. Zhang were involved in the conception and study design; Y. Bian, S. Ma, M. Ge, H. Li, S. Zheng, Z. Gu, H. Feng, Z. Yu, C. Huang and H. Zhang conducted the study; Y Bian, S Ma, Q. Yao, T. Hu and Z. Yu conducted data analyses; Y. Bian, S. Ma, L. Zhao and L. Miao were responsible for writing the manuscript. All authors reviewed and approved the manuscript.

Acknowledgments

The authors would like to thank the subjects who took part in the trial, as well as the staff who assisted with the trial at the site. The authors would also like to thank American Journal Experts for medical writing support. The trial is registered at ClinicalTrials.gov (NCT05716126).

Data availability statement

The data that support the findings of this study are available from the correspondence author upon reasonable request.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Reviewer disclosures

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

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/13543784.2024.2305134.

Additional information

Funding

This work was funded by the National Key New Drug Creation Special Programs [2017ZX09304-021], Hospital Pharmacy Committee of Chinese Pharmaceutical Association [CPA-Z05-ZC-2021-002], National Natural Science Foundation of China [82304633] and Qilu Pharmaceutical Co., Ltd.