Dosage Strategy of Linezolid According to the Trough Concentration Target and Renal Function in Chinese Critically Ill Patients
Background: Linezolid is associated with myelosuppression, which may cause failure in optimally treating bacterial infections. The study aimed to define the pharmacokinetic/toxicodynamic (PK/TD) threshold for critically ill patients and to identify a dosing strategy for critically ill patients with...
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| Format: | Article |
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.844567/full |
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| author | Fan Wu Xiao-Shan Zhang Ying Dai Zi-Ye Zhou Chun-Hong Zhang Lu Han Fang-Min Xu Ye-Xuan Wang Da-Wei Shi Guan-Yang Lin Xu-Ben Yu Fang Chen |
| author_facet | Fan Wu Xiao-Shan Zhang Ying Dai Zi-Ye Zhou Chun-Hong Zhang Lu Han Fang-Min Xu Ye-Xuan Wang Da-Wei Shi Guan-Yang Lin Xu-Ben Yu Fang Chen |
| author_sort | Fan Wu |
| collection | DOAJ |
| description | Background: Linezolid is associated with myelosuppression, which may cause failure in optimally treating bacterial infections. The study aimed to define the pharmacokinetic/toxicodynamic (PK/TD) threshold for critically ill patients and to identify a dosing strategy for critically ill patients with renal insufficiency.Methods: The population pharmacokinetic (PK) model was developed using the NONMEM program. Logistic regression modeling was conducted to determine the toxicodynamic (TD) threshold of linezolid-induced myelosuppression. The dosing regimen was optimized based on the Monte Carlo simulation of the final model.Results: PK analysis included 127 linezolid concentrations from 83 critically ill patients at a range of 0.25–21.61 mg/L. Creatinine clearance (CrCL) was identified as the only covariate of linezolid clearance that significantly explained interindividual variability. Thirty-four (40.97%) of the 83 patients developed linezolid-associated myelosuppression. Logistic regression analysis showed that the trough concentration (Cmin) was a significant predictor of myelosuppression in critically patients, and the threshold for Cmin in predicting myelosuppression with 50% probability was 7.8 mg/L. The Kaplan–Meier plot revealed that the overall median time from the initiation of therapy to the development of myelosuppression was 12 days. Monte Carlo simulation indicated an empirical dose reduction to 600 mg every 24 h was optimal to balance the safety and efficacy in critically ill patients with CrCL of 30–60 ml/min, 450 mg every 24 h was the alternative for patients with CrCL <30 ml/min, and 600 mg every 12 h was recommended for patients with CrCL ≥60 ml/min.Conclusion: Renal function plays a significant role in linezolid PKs for critically ill patients. A dose of 600 mg every 24 h was recommended for patients with CrCL <60 ml/min to minimize linezolid-induced myelosuppression. |
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| id | doaj.art-44d10f8c8cd04fa189b234dace9c47a9 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T04:15:18Z |
| publishDate | 2022-04-01 |
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| spelling | doaj.art-44d10f8c8cd04fa189b234dace9c47a92022-12-22T03:02:59ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-04-011310.3389/fphar.2022.844567844567Dosage Strategy of Linezolid According to the Trough Concentration Target and Renal Function in Chinese Critically Ill PatientsFan Wu0Xiao-Shan Zhang1Ying Dai2Zi-Ye Zhou3Chun-Hong Zhang4Lu Han5Fang-Min Xu6Ye-Xuan Wang7Da-Wei Shi8Guan-Yang Lin9Xu-Ben Yu10Fang Chen11Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Pharmacy, Wenzhou Medical University, Wenzhou, ChinaDepartment of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Pharmacy, Wenzhou Medical University, Wenzhou, ChinaDepartment of Pharmacy, Wenzhou Medical University, Wenzhou, ChinaDepartment of Pharmacy, Wenzhou Medical University, Wenzhou, ChinaDepartment of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Pharmacy, The First Affiliated Hospital of Xiamen University, Xiamen, ChinaBackground: Linezolid is associated with myelosuppression, which may cause failure in optimally treating bacterial infections. The study aimed to define the pharmacokinetic/toxicodynamic (PK/TD) threshold for critically ill patients and to identify a dosing strategy for critically ill patients with renal insufficiency.Methods: The population pharmacokinetic (PK) model was developed using the NONMEM program. Logistic regression modeling was conducted to determine the toxicodynamic (TD) threshold of linezolid-induced myelosuppression. The dosing regimen was optimized based on the Monte Carlo simulation of the final model.Results: PK analysis included 127 linezolid concentrations from 83 critically ill patients at a range of 0.25–21.61 mg/L. Creatinine clearance (CrCL) was identified as the only covariate of linezolid clearance that significantly explained interindividual variability. Thirty-four (40.97%) of the 83 patients developed linezolid-associated myelosuppression. Logistic regression analysis showed that the trough concentration (Cmin) was a significant predictor of myelosuppression in critically patients, and the threshold for Cmin in predicting myelosuppression with 50% probability was 7.8 mg/L. The Kaplan–Meier plot revealed that the overall median time from the initiation of therapy to the development of myelosuppression was 12 days. Monte Carlo simulation indicated an empirical dose reduction to 600 mg every 24 h was optimal to balance the safety and efficacy in critically ill patients with CrCL of 30–60 ml/min, 450 mg every 24 h was the alternative for patients with CrCL <30 ml/min, and 600 mg every 12 h was recommended for patients with CrCL ≥60 ml/min.Conclusion: Renal function plays a significant role in linezolid PKs for critically ill patients. A dose of 600 mg every 24 h was recommended for patients with CrCL <60 ml/min to minimize linezolid-induced myelosuppression.https://www.frontiersin.org/articles/10.3389/fphar.2022.844567/fulllinezolidpopulation pharmacokineticsmyelosuppressiondosage strategyrenal function |
| spellingShingle | Fan Wu Xiao-Shan Zhang Ying Dai Zi-Ye Zhou Chun-Hong Zhang Lu Han Fang-Min Xu Ye-Xuan Wang Da-Wei Shi Guan-Yang Lin Xu-Ben Yu Fang Chen Dosage Strategy of Linezolid According to the Trough Concentration Target and Renal Function in Chinese Critically Ill Patients Frontiers in Pharmacology linezolid population pharmacokinetics myelosuppression dosage strategy renal function |
| title | Dosage Strategy of Linezolid According to the Trough Concentration Target and Renal Function in Chinese Critically Ill Patients |
| title_full | Dosage Strategy of Linezolid According to the Trough Concentration Target and Renal Function in Chinese Critically Ill Patients |
| title_fullStr | Dosage Strategy of Linezolid According to the Trough Concentration Target and Renal Function in Chinese Critically Ill Patients |
| title_full_unstemmed | Dosage Strategy of Linezolid According to the Trough Concentration Target and Renal Function in Chinese Critically Ill Patients |
| title_short | Dosage Strategy of Linezolid According to the Trough Concentration Target and Renal Function in Chinese Critically Ill Patients |
| title_sort | dosage strategy of linezolid according to the trough concentration target and renal function in chinese critically ill patients |
| topic | linezolid population pharmacokinetics myelosuppression dosage strategy renal function |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.844567/full |
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