Do Critically Ill Patients Undergoing Continuous Renal Replacement Therapy Require Ceftaroline Dosage Adjustments? Ceftaroline PopPK Model and Dosage Simulations with the Probability of Target Attainment Analysis Based on Retrospective Data
<b>Objectives</b>: We aimed to develop a population pharmacokinetic (PopPK) model and evaluate dosing regimens for different renal clearances and continuous renal replacement therapy (CRRT) settings. <b>Methods</b>: Data were collected from four studies in intensive care unit...
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2025-03-01
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| author | Arkadiusz Adamiszak Krzysztof Pietrzkiewicz Alicja Bartkowska-Śniatkowska Piotr Smuszkiewicz Krzysztof Kusza Edmund Grześkowiak Agnieszka Bienert |
| author_facet | Arkadiusz Adamiszak Krzysztof Pietrzkiewicz Alicja Bartkowska-Śniatkowska Piotr Smuszkiewicz Krzysztof Kusza Edmund Grześkowiak Agnieszka Bienert |
| author_sort | Arkadiusz Adamiszak |
| collection | DOAJ |
| description | <b>Objectives</b>: We aimed to develop a population pharmacokinetic (PopPK) model and evaluate dosing regimens for different renal clearances and continuous renal replacement therapy (CRRT) settings. <b>Methods</b>: Data were collected from four studies in intensive care unit (ICU) adult patients receiving 400–600 mg of ceftaroline every 8–12 h in a one-hour infusion. The PopPK model was developed according to non-linear mixed effects modeling implemented in Monolix 2024R1. To investigate dosing recommendations, Monte Carlo simulations and probability of target attainment (PTA) analysis were performed in Simulx 2024R1. <b>Results</b>: We collected 296 plasma concentrations from 29 non-CRRT patients and 24 pre-filter (systemic), 23 post-filter, and 23 effluent concentrations from four CRRT patients using WebPlotDigitizer (Version 4.7). A five-compartment model, with the first-order elimination from the central compartment and additional elimination with the effluent during CRRT, best described the ceftaroline concentrations. Creatinine clearance (<i>Cl<sub>Cr</sub></i>) was identified as a covariate on the clearance of elimination (<i>Cl</i>) and CRRT modality on the central and peripheral compartments’ volumes and intercompartmental clearance. The results of dosage simulations for different CRRT modalities and <i>Cl<sub>Cr</sub></i>, <i>S. pneumoniae</i> (MIC = 0.25 mg/L) and methicillin-resistant <i>S. aureus</i> (MRSA) (MIC = 1 mg/L) infections, and assumed 100%ƒT<sub>>MIC</sub> target, revealed that registered ceftaroline dosages are sufficient to achieve assumed PTA, except MRSA infection in patients with augmented renal clearance (ARC). <b>Conclusions</b>: Our successfully developed model allows flexible PK simulations of ceftaroline, including real-time changes in settings and even temporary or permanent cessation of CRRT. However, the results of our study warrant clinical validation and should be used with caution primarily due to the limited CRRT patient number included in the analysis. |
| format | Article |
| id | doaj-art-45a402dd8ef941aa9f95a99ed4afc79a |
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| language | English |
| publishDate | 2025-03-01 |
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| spelling | doaj-art-45a402dd8ef941aa9f95a99ed4afc79a2025-08-20T02:28:40ZengMDPI AGAntibiotics2079-63822025-03-0114434710.3390/antibiotics14040347Do Critically Ill Patients Undergoing Continuous Renal Replacement Therapy Require Ceftaroline Dosage Adjustments? Ceftaroline PopPK Model and Dosage Simulations with the Probability of Target Attainment Analysis Based on Retrospective DataArkadiusz Adamiszak0Krzysztof Pietrzkiewicz1Alicja Bartkowska-Śniatkowska2Piotr Smuszkiewicz3Krzysztof Kusza4Edmund Grześkowiak5Agnieszka Bienert6Department of Pharmacology, Poznan University of Medical Sciences, 60-806 Poznan, PolandDepartment of Paediatric Anaesthesiology and Intensive Therapy, Poznan University of Medical Sciences, 60-572 Poznan, PolandDepartment of Paediatric Anaesthesiology and Intensive Therapy, Poznan University of Medical Sciences, 60-572 Poznan, PolandDepartment of Anesthesiology, Intensive Therapy and Pain Management, Poznan University of Medical Sciences, 60-352 Poznan, PolandDepartment of Anesthesiology, Intensive Therapy and Pain Management, Poznan University of Medical Sciences, 60-352 Poznan, PolandDepartment of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, 60-806 Poznan, PolandDepartment of Pharmacology, Poznan University of Medical Sciences, 60-806 Poznan, Poland<b>Objectives</b>: We aimed to develop a population pharmacokinetic (PopPK) model and evaluate dosing regimens for different renal clearances and continuous renal replacement therapy (CRRT) settings. <b>Methods</b>: Data were collected from four studies in intensive care unit (ICU) adult patients receiving 400–600 mg of ceftaroline every 8–12 h in a one-hour infusion. The PopPK model was developed according to non-linear mixed effects modeling implemented in Monolix 2024R1. To investigate dosing recommendations, Monte Carlo simulations and probability of target attainment (PTA) analysis were performed in Simulx 2024R1. <b>Results</b>: We collected 296 plasma concentrations from 29 non-CRRT patients and 24 pre-filter (systemic), 23 post-filter, and 23 effluent concentrations from four CRRT patients using WebPlotDigitizer (Version 4.7). A five-compartment model, with the first-order elimination from the central compartment and additional elimination with the effluent during CRRT, best described the ceftaroline concentrations. Creatinine clearance (<i>Cl<sub>Cr</sub></i>) was identified as a covariate on the clearance of elimination (<i>Cl</i>) and CRRT modality on the central and peripheral compartments’ volumes and intercompartmental clearance. The results of dosage simulations for different CRRT modalities and <i>Cl<sub>Cr</sub></i>, <i>S. pneumoniae</i> (MIC = 0.25 mg/L) and methicillin-resistant <i>S. aureus</i> (MRSA) (MIC = 1 mg/L) infections, and assumed 100%ƒT<sub>>MIC</sub> target, revealed that registered ceftaroline dosages are sufficient to achieve assumed PTA, except MRSA infection in patients with augmented renal clearance (ARC). <b>Conclusions</b>: Our successfully developed model allows flexible PK simulations of ceftaroline, including real-time changes in settings and even temporary or permanent cessation of CRRT. However, the results of our study warrant clinical validation and should be used with caution primarily due to the limited CRRT patient number included in the analysis.https://www.mdpi.com/2079-6382/14/4/347ceftarolinecontinuous renal replacement therapypopulation pharmacokineticsMonte Carlo simulationsprobability of target attainmentintensive care unit |
| spellingShingle | Arkadiusz Adamiszak Krzysztof Pietrzkiewicz Alicja Bartkowska-Śniatkowska Piotr Smuszkiewicz Krzysztof Kusza Edmund Grześkowiak Agnieszka Bienert Do Critically Ill Patients Undergoing Continuous Renal Replacement Therapy Require Ceftaroline Dosage Adjustments? Ceftaroline PopPK Model and Dosage Simulations with the Probability of Target Attainment Analysis Based on Retrospective Data Antibiotics ceftaroline continuous renal replacement therapy population pharmacokinetics Monte Carlo simulations probability of target attainment intensive care unit |
| title | Do Critically Ill Patients Undergoing Continuous Renal Replacement Therapy Require Ceftaroline Dosage Adjustments? Ceftaroline PopPK Model and Dosage Simulations with the Probability of Target Attainment Analysis Based on Retrospective Data |
| title_full | Do Critically Ill Patients Undergoing Continuous Renal Replacement Therapy Require Ceftaroline Dosage Adjustments? Ceftaroline PopPK Model and Dosage Simulations with the Probability of Target Attainment Analysis Based on Retrospective Data |
| title_fullStr | Do Critically Ill Patients Undergoing Continuous Renal Replacement Therapy Require Ceftaroline Dosage Adjustments? Ceftaroline PopPK Model and Dosage Simulations with the Probability of Target Attainment Analysis Based on Retrospective Data |
| title_full_unstemmed | Do Critically Ill Patients Undergoing Continuous Renal Replacement Therapy Require Ceftaroline Dosage Adjustments? Ceftaroline PopPK Model and Dosage Simulations with the Probability of Target Attainment Analysis Based on Retrospective Data |
| title_short | Do Critically Ill Patients Undergoing Continuous Renal Replacement Therapy Require Ceftaroline Dosage Adjustments? Ceftaroline PopPK Model and Dosage Simulations with the Probability of Target Attainment Analysis Based on Retrospective Data |
| title_sort | do critically ill patients undergoing continuous renal replacement therapy require ceftaroline dosage adjustments ceftaroline poppk model and dosage simulations with the probability of target attainment analysis based on retrospective data |
| topic | ceftaroline continuous renal replacement therapy population pharmacokinetics Monte Carlo simulations probability of target attainment intensive care unit |
| url | https://www.mdpi.com/2079-6382/14/4/347 |
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