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已发表论文
基于生理学的利奈唑胺药代动力学模型及肾功能不全儿科患者的剂量优化
Authors Lou JQ, Huo BN, Yang Y, Wang SF, Zhang LD, Jia YT, Song L
Received 20 March 2025
Accepted for publication 1 September 2025
Published 17 September 2025 Volume 2025:19 Pages 8427—8440
DOI https://doi.org/10.2147/DDDT.S525400
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Manfred Ogris
Jia-Qi Lou,1 Ben-Nian Huo,1 Ya Yang,1 Shu-Feng Wang,2 Lu-Dan Zhang,1 Yun-Tao Jia,1 Lin Song1
1Department of Pharmacy, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, People’s Republic of China; 2Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, 400038, People’s Republic of China
Correspondence: Yun-Tao Jia, Email jiayuntaomail@hospital.cqmu.edu.cn Lin Song, Email songlin@hospital.cqmu.edu.cn
Objective: Linezolid (LZD), a commonly used antimicrobial agent in clinical practice, has not undergone adequate pharmacokinetic (PK) assessment in pediatric populations with renal impairment (RI). Physiologically based pharmacokinetic (PBPK) modeling provides unique benefits for investigating drug pharmacokinetics in specific patient groups. This study aimed to employ the PBPK model to refine and optimize the therapeutic dosing protocol of LZD for RI pediatric patients.
Methods: The model was developed and validated for both healthy adults and RI adults, which was subsequently adapted for pediatric applications. Upon verification of the pediatric Based on clinical PK data and real-world study findings, the PBPK model demonstrated precise prediction of LZD exposure in pediatric populations with varying degrees of RI, encompassing weight- and age-associated PK variations.
Results: The PBPK modeling simulations exhibited robust agreement with observational data for LZD across both oral and intravenous delivery routes under diverse dosing protocols, as evidenced by the fold error (FE) always between 0.5 and 2 times, geometric mean fold error (GMFE) was less than 2.0 and mean absolute prediction error (MAPE) was within 100%. Pediatric populations with severe or end-stage RI exhibited 1.21-fold and 1.28-fold elevations in plasma concentration-time curve (AUC) values, respectively, relative to healthy pediatric counterparts when administered equivalent 10 mg/kg LZD doses. Pharmacodynamic analysis confirmed that the proposed dosing regimens— 8 mg/kg every 8 hours for children with severe or end-stage RI —were effective in achieving the target AUC0-24/MIC ratio of ≥ 80 at a susceptible inhibitory concentration of ≤ 2 mg/L.
Conclusion: Our model provides a predictive instrument to enhance precision in determining therapeutic LZD dosage regimens for pediatric populations through systematic integration of developmental PK parameters.
Keywords: pediatric, physiologically based pharmacokinetic model, renal impairment, linezolid, pharmacodynamics
1Department of Pharmacy, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, People’s Republic of China; 2Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, 400038, People’s Republic of China
Correspondence: Yun-Tao Jia, Email jiayuntaomail@hospital.cqmu.edu.cn Lin Song, Email songlin@hospital.cqmu.edu.cn
Objective: Linezolid (LZD), a commonly used antimicrobial agent in clinical practice, has not undergone adequate pharmacokinetic (PK) assessment in pediatric populations with renal impairment (RI). Physiologically based pharmacokinetic (PBPK) modeling provides unique benefits for investigating drug pharmacokinetics in specific patient groups. This study aimed to employ the PBPK model to refine and optimize the therapeutic dosing protocol of LZD for RI pediatric patients.
Methods: The model was developed and validated for both healthy adults and RI adults, which was subsequently adapted for pediatric applications. Upon verification of the pediatric Based on clinical PK data and real-world study findings, the PBPK model demonstrated precise prediction of LZD exposure in pediatric populations with varying degrees of RI, encompassing weight- and age-associated PK variations.
Results: The PBPK modeling simulations exhibited robust agreement with observational data for LZD across both oral and intravenous delivery routes under diverse dosing protocols, as evidenced by the fold error (FE) always between 0.5 and 2 times, geometric mean fold error (GMFE) was less than 2.0 and mean absolute prediction error (MAPE) was within 100%. Pediatric populations with severe or end-stage RI exhibited 1.21-fold and 1.28-fold elevations in plasma concentration-time curve (AUC) values, respectively, relative to healthy pediatric counterparts when administered equivalent 10 mg/kg LZD doses. Pharmacodynamic analysis confirmed that the proposed dosing regimens— 8 mg/kg every 8 hours for children with severe or end-stage RI —were effective in achieving the target AUC0-24/MIC ratio of ≥ 80 at a susceptible inhibitory concentration of ≤ 2 mg/L.
Conclusion: Our model provides a predictive instrument to enhance precision in determining therapeutic LZD dosage regimens for pediatric populations through systematic integration of developmental PK parameters.
Keywords: pediatric, physiologically based pharmacokinetic model, renal impairment, linezolid, pharmacodynamics