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Trilaciclib dosage in Chinese patients with extensive-stage small cell lung cancer: a pooled pharmacometrics analysis

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

This study aimed to analyze potential ethnic disparities in the dose–exposure–response relationships of trilaciclib, a first-in-class intravenous cyclin-dependent kinase 4/6 inhibitor for treating chemotherapy-induced myelosuppression in patients with extensive-stage small cell lung cancer (ES-SCLC). This investigation focused on characterizing these relationships in both Chinese and non-Chinese patients to further refine the dosing regimen for trilaciclib in Chinese patients with ES-SCLC. Population pharmacokinetic (PopPK) and exposure–response (E–R) analyses were conducted using pooled data from four randomized phase 2/3 trials involving Chinese and non-Chinese patients with ES-SCLC. PopPK analysis revealed that trilaciclib clearance in Chinese patients was approximately 17% higher than that in non-Chinese patients with ES-SCLC. Sex and body surface area influenced trilaciclib pharmacokinetics in both populations but did not exert a significant clinical impact. E–R analysis demonstrated that trilaciclib exposure increased with a dosage escalation from 200 to 280 mg/m2, without notable changes in myeloprotective or antitumor efficacy. However, the incidence of infusion site reactions, headaches, and phlebitis/thrombophlebitis rose with increasing trilaciclib exposure in both Chinese and non-Chinese patients with ES-SCLC. These findings suggest no substantial ethnic disparities in the dose–exposure–response relationship between Chinese and non-Chinese patients. They support the adoption of a 240-mg/m2 intravenous 3-day or 5-day dosing regimen for trilaciclib in Chinese patients with ES-SCLC.

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Fig. 1: Goodness-of-fit plots of the base and final population pharmacokinetic model.
Fig. 2: Prediction-corrected visual predictive check plots of the final population pharmacokinetic model.
Fig. 3: Influences of ethnicity and other identified covariates trilaciclib exposure under the dosing regimen of 240 mg/m2 given on days 1–3 in a 21-day cycle.
Fig. 4: Linear model fits for the relationship between the area under the concentration-time curve (AUC) of trilaciclib and absolute neutrophil count (ANC) nadir in cycle 1.
Fig. 5: Logistic regression model fits for the relationship between the area under the concentration–time curve (AUC) of trilaciclib and efficacy endpoints.
Fig. 6: Kaplan–Meier plots for the hazard rate of progression-free survival.
Fig. 7: Kaplan–Meier plots for the hazard rate of overall survival.
Fig. 8: Logistic regression model fits for the relationship between the area under the concentration-time curve (AUC) of trilaciclib and safety endpoints for all the four clinical studies.

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Acknowledgements

We would like to thank all the subjects in these trials. Special thanks go to Dr. Jun-jie Ding from University of Oxford and Dr. Liang Li from Gracell Biotechnologies Group for their valuable comments. We thank Editage (www.editage.cn) for English language editing. This study was sponsored by Simcere Zaiming Pharmaceutical Co. Ltd.

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  1. These authors contributed equally: Hao-ran Dai, Yang Yang, Chen-yu Wang

Authors and Affiliations

  1. Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China

    Hao-ran Dai, Chen-yu Wang, Yue-ting Chen, Yi-fan Cui & Zheng Jiao

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

    Yang Yang, Pei-jing Li, Jia Chen & Chen Yang

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Contributions

HRD: Methodology, Software, Formal analysis, Validation, Visualization, Writing–Original Draft, and Writing–Review and Editing; YY: Methodology, Investigation, Data curation, Formal analysis, Validation, Supervision, Writing–Original Draft, and Writing–Review and Editing; CYW: Methodology, Software, Validation, Visualization, Investigation, Writing–Original Draft, and Writing–Review and Editing; YTC: Methodology, Software, Investigation, and Writing–Review and Editing; YFC: Methodology, Software, Investigation; PJL: Investigation, Data curation, Supervision, and Writing–Review and Editing; JC: Investigation, Supervision, and Writing–Review and Editing; CY: Supervision, and Writing–Review and Editing; ZJ: Conceptualization, Supervision, Methodology, Writing–Original Draft, and Writing–Review and Editing. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

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Correspondence to Zheng Jiao.

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YY, PJL, JC, and CY are employees of Simcere Zaiming Pharmaceutical Co. Ltd. Other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Dai, Hr., Yang, Y., Wang, Cy. et al. Trilaciclib dosage in Chinese patients with extensive-stage small cell lung cancer: a pooled pharmacometrics analysis. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01297-6

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