https://orcid.org/0000-0001-9911-2181
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ABSTRACT
Background
SIM0295, a novel inhibitor of human uric acid transporter 1 (hURAT1), is used to treat patients with gout and hyperuricemia. This study aimed to develop population pharmacokinetics and pharmacodynamics (popPK/PD) models of SIM0295 and explore potential covariates to inform clinical drug development.
Research design and methods
Data were obtained from four phase I studies conducted in healthy Korean and Chinese subjects and two phase II studies conducted in Korean patients with gout and hyperuricemia. The popPK/PD model of SIM0295 was developed using nonlinear mixed effects modeling.
Results
SIM0295 pharmacokinetics was described using a two-compartment model with the absorption of four transit compartments and first-order elimination. PK parameters were normalized to weight via allometric scaling. Food was identified as a factor significantly affecting the absorption rate, with no clinical relevance. The sigmoid Emax model with a semi-mechanism of inhibition of serum uric acid (sUA) reabsorption was used to describe the exposure-response relationship. Additionally, Monte Carlo simulations demonstrated that approimately 9 mg/day of SIM0295 for 7 days could achieve the maximum decrease in sUA.
Conclusion
The established popPK/PD model characterized the dose-exposure-response relationship for SIM0295 in healthy subjects and patients with gout and hyperuricemia and could be used to inform the drug development.
Acknowledgments
We would like to thank all the subjects in these trials. We would like to thank Editage (www.editage.cn) for English language editing.
Declaration of interest
This study was sponsored by Jiangsu Simcere Pharmaceutical Co. Ltd. Yang Yang, Shansen Xu, Pan Shu, Xiaoyu Zhang, and Qin Huang are employees of Jiangsu Simcere Pharmaceutical Co. Ltd. Zheng Jiao received consulting fees from Takeda, AstraZeneca and Pharmaron.
Data availability statement
Due to the nature of the research, commercial supporting data is not available.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Author contributions
Yue-ting Chen: Methodology, Software, Writing-Original Draft, and Writing-Review and Editing; Yang Yang: Methodology, Investigation, Supervision, and Writing-Original Draft – Review and Editing; Shan-sen Xu: Investigation, Resources, and Writing – Review and Editing. Chen-yu Wang: Methodology, Software, Investigation, and Writing-Review and Editing. Pan Shu, Xiao-yu Zhang, Qin Huang, and Jin Sook Kim: Investigation, Conceptualization, Resources. Zheng Jiao: Conceptualization, Methodology, Writing-Original Draft, Supervision, and Writing-Review and Editing.
Ethical statement
The studies involving human participants were reviewed and approved by local ethics committees. The patients/participants provided their written informed consent to participate in this study.
Clinical trial registration
he trials are registered at the Clinical Trail and Chinese Clinical Trial website. (CTR20210289、CTR20202694、NCT01953497、NCT02524678、NCT02290210、NCT02557126)
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/13543784.2023.2212153.