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19F qNMR based pharmacokinetics, metabolism and mass balance studies of SARS-CoV-2-3CL protease inhibitor simnotrelvir (SIM0417) in humans

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Simnotrelvir (SIM0417), an inhibitor of the 3CL protease of SARS-CoV-2, has been identified as a CYP3A sensitive substrate. This study investigated the pharmacokinetics, metabolism, and mass balance of simnotrelvir following a single oral dose of 750 mg in six healthy Chinese male subjects, co-administered with four doses of 100 mg ritonavir. Analysis using 19F qNMR combined with LC-MS/MS showed that the parent drug M0 constituted over 90% of the drug-related components in plasma. Of the administered dose, 55.4% (54.3% of M0) was recovered in urine, while 36.7% (4.57% of M0) was excreted in feces. UPLC/Q-TOF MS was used to identify metabolites in human plasma, urine and feces. Notably, oxidative metabolites catalyzed by CYP3A were scarcely detected in these matrixes. The amide hydrolyzed metabolite M9 and the cyano hydrolyzed metabolite M10 were recognized as the predominant metabolites, with the main excretion being through feces (19.0% and 12.7% of the administered dose, respectively). In vitro experiments indicated that M10 is primarily formed in the duodenum and jejunum, with further metabolism to M9 by microbiota in the large intestine. Overall, the co-administration of simnotrelvir with ritonavir led to predominant metabolism by intestinal enzymes or microbiota, resulting in hydrolyzed metabolites. These findings highlight the critical role of intestinal metabolism in the pharmacokinetics of simnotrelvir and emphasize the need to consider interactions with antibiotics and individual differences of intestinal microbiota.

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Fig. 1: Metabolic profiles of simnotrelvir in human plasma, urine and feces by UPLC/Q-TOF MS.
Fig. 2: Proposed metabolic pathways of simnotrelvir in human plasma, urine and feces.
Fig. 3: Metabolism of simnotrelvir in vitro.
Fig. 4: Concentration-time curves of simnotrelvir and its metabolites in human plasma following a single dose of 750 mg simnotrelvir co-administered with four doses of 100 mg ritonavir.
Fig. 5: Formation of M10 and M9 in tissue homogenates, tissue contents, and feces.
Fig. 6: Formation of M10 in duodenum homogenate or jejunum content with various inhibitors.

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References

  1. World Health Organization [homepage on the Internet].data.who.int, WHO Coronavirus (COVID-19) dashboard > Cases [Dashboard]. [updated 2024 May 5; cited 2024 May 23] Available from: https://data.who.int/dashboards/covid19/cases?n=c.

  2. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382:727–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, et al. Structure of M(pro) from SARS-CoV-2 and discovery of its inhibitors. Nature. 2020;582:289–93.

    Article  CAS  PubMed  Google Scholar 

  5. Cao B, Wang Y, Lu HZ, Huang CL, Yang YM, Shang LH, et al. Oral simnotrelvir for adult patients with mild-to-moderate Covid-19. N Engl J Med. 2024;390:230–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wang FX, Xiao W, Tang YM, Cao ML, Shu D, Asakawa T, et al. Efficacy and safety of SIM0417 (SSD8432) plus ritonavir for COVID-19 treatment: a randomised, double-blind, placebo- controlled, phase 1b trial. Lancet Reg Health West Pac 2023;38:100835.

  7. Jiang X, Su H, Shang W, Zhou F, Zhang Y, Zhao W, et al. Structure-based development and preclinical evaluation of the SARS-CoV-23C-like protease inhibitor simnotrelvir. Nat Commun. 2023;14:6463.

  8. Yang XM, Yang Y, Yao BF, Ye PP, Xu Y, Peng SP, et al. A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects. Eur J Pharm Sci. 2023;191:106598.

  9. Ramamoorthy A, Bende G, Chow ECY, Dimova H, Hartman N, Jean D, et al. Human radiolabeled mass balance studies supporting the FDA approval of new drugs. Clin Transl Sci. 2022;15:2567–75.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Pearson D, Garnier M, Luneau A, James AD, Walles M. 19)F-NMR-based determination of the absorption, metabolism and excretion of the oral phosphatidylinositol-3-kinase (PI3K) delta inhibitor leniolisib (CDZ173) in healthy volunteers. Xenobiotica. 2019;49:953–60.

    Article  CAS  PubMed  Google Scholar 

  11. Singh RSP, Walker GS, Kadar EP, Cox LM, Eng H, Sharma R, et al. Metabolism and excretion of nirmatrelvir in humans using quantitative fluorine nuclear magnetic resonance spectroscopy: a novel approach for accelerating drug development. Clin Pharmacol Ther. 2022;112:1201–6.

    Article  CAS  PubMed  Google Scholar 

  12. James AD, Marvalin C, Luneau A, Meissner A, Camenisch G. Comparison of 19F NMR and 14C measurements for the assessment of ADME of BYL719 (Alpelisib) in humans. Drug Metab Dispos. 2017;45:900–7.

    Article  CAS  PubMed  Google Scholar 

  13. U.S. Food and Drug Administration: Bioanalytical Method Validation Guidance for Industry. 2018; Available from: https://www.fda.gov/media/70858/download.

  14. U.S. Food and Drug Administration: Clinical Pharmacology Considerations for Human Radiolabeled Mass Balance Studies. 2022; Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-pharmacology-considerations-human-radiolabeled-mass-balance-studies.

  15. Asakura M, Fukami T, Nakajima M, Fujii H, Atsuda K, Itoh T, et al. Hepatic dipeptidyl peptidase-4 controls pharmacokinetics of vildagliptin in vivo. Drug Metab Dispos. 2017;45:237–45.

    Article  CAS  PubMed  Google Scholar 

  16. Kong FD, Pang XY, Zhao JH, Deng P, Zheng MY, Zhong DF, et al. Hydrolytic metabolism of cyanopyrrolidine DPP-4 inhibitors mediated by dipeptidyl peptidases. Drug Metab Dispos. 2019;47:238–48.

    Article  CAS  PubMed  Google Scholar 

  17. Wang K, Zhang ZW, Hang J, Liu J, Guo FS, Ding Y, et al. Microbial-host-isozyme analyses reveal microbial DPP4 as a potential antidiabetic target. Science. 2023;381:501.

    Article  Google Scholar 

  18. Tahara A, Matsuyama-Yokono A, Nakano R, Someya Y, Hayakawa M, Shibasaki M. Antihyperglycemic effects of ASP8497 in streptozotocin-nicotinamide induced diabetic rats: comparison with other dipeptidyl peptidase-IV inhibitors. Pharmacol Rep. 2009;61:899–908.

    Article  CAS  PubMed  Google Scholar 

  19. Singh RSP, Toussi SS, Hackman F, Chan PL, Rao R, Allen R, et al. Innovative randomized phase I study and dosing regimen selection to accelerate and inform pivotal COVID-19 trial of nirmatrelvir. Clin Pharmacol Ther. 2022;112:101–11.

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Acknowledgements

This research was partially supported by the National Natural Science Foundation of China (No. 82073924) and grants from State Key Laboratory of Drug Research. We acknowledge the clinical teams at the First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital for conducting the human mass balance study of simnotrelvir (Principal investigator: Prof. Wei Zhao). We would also like to acknowledge EditSprings (https://www.editsprings.cn) for the expert linguistic services provided.

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  1. These authors contributed equally: Ze-yu Wang, Yong-mei Ren

Authors and Affiliations

  1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Ze-yu Wang, Yong-mei Ren, Meng-xiao Dong, Yun Li & Xiao-yan Chen

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Ze-yu Wang, Nai-xia Zhang & Xiao-yan Chen

  3. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Shu-wei Hu & Nai-xia Zhang

  4. State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, 210042, China

    Yang Yang, Zi-jia Guo, Shan-sen Xu, Jia Chen & Aik Han Goh

  5. Simcere Zaiming Pharmaceutical Co. Ltd., Nanjing, 210042, China

    Yang Yang & Jia Chen

  6. Jiangsu Simcere Pharmaceutical Co., Ltd, Nanjing, 210042, China

    Zi-jia Guo, Shan-sen Xu & Aik Han Goh

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Contributions

ZYW, YMR, and XYC designed and performed research, analyzed data and wrote the paper; SWH, NXZ, MXD, and YL performed research and analyzed data; YY, ZJG, SSX, JC, and AHG contributed the test drug and extended financial support.

Corresponding author

Correspondence to Xiao-yan Chen.

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Competing interests

YY and JC are employees of Simcere Zaiming Pharmaceutical Co. Ltd. ZJG, SSX, and AHG are employees of Jiangsu Simcere Pharmaceutical Co., Ltd. The other authors declare that they have no competing interests.

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Wang, Zy., Ren, Ym., Hu, Sw. et al. 19F qNMR based pharmacokinetics, metabolism and mass balance studies of SARS-CoV-2-3CL protease inhibitor simnotrelvir (SIM0417) in humans. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01393-7

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