دورية أكاديمية
Predictive Performance of Physiologically Based Pharmacokinetic Modelling of Beta-Lactam Antibiotic Concentrations in Adipose, Bone, and Muscle Tissues.
| العنوان: | Predictive Performance of Physiologically Based Pharmacokinetic Modelling of Beta-Lactam Antibiotic Concentrations in Adipose, Bone, and Muscle Tissues. |
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| المؤلفون: | De Sutter PJ; Laboratory of Medical Biochemistry and Clinical Analysis, Department of Bioanalysis, Faculty of Pharmaceutical Sciences (P-J.DS., E.G., A.V.), Department of Basic and Applied Medical Science, Faculty of Medicine and Health Sciences (P.D-C), Ghent University, Ghent, Belgium; Department of Pharmacy and Department of Pediatric Intensive Care, Ghent University Hospital, Ghent, Belgium (P.D-C.); and Certara UK Limited, Sheffield, United Kingdom (T.N.J., H.M.) pieterjan.desutter@ugent.be., De Cock P; Laboratory of Medical Biochemistry and Clinical Analysis, Department of Bioanalysis, Faculty of Pharmaceutical Sciences (P-J.DS., E.G., A.V.), Department of Basic and Applied Medical Science, Faculty of Medicine and Health Sciences (P.D-C), Ghent University, Ghent, Belgium; Department of Pharmacy and Department of Pediatric Intensive Care, Ghent University Hospital, Ghent, Belgium (P.D-C.); and Certara UK Limited, Sheffield, United Kingdom (T.N.J., H.M.)., Johnson TN; Laboratory of Medical Biochemistry and Clinical Analysis, Department of Bioanalysis, Faculty of Pharmaceutical Sciences (P-J.DS., E.G., A.V.), Department of Basic and Applied Medical Science, Faculty of Medicine and Health Sciences (P.D-C), Ghent University, Ghent, Belgium; Department of Pharmacy and Department of Pediatric Intensive Care, Ghent University Hospital, Ghent, Belgium (P.D-C.); and Certara UK Limited, Sheffield, United Kingdom (T.N.J., H.M.)., Musther H; Laboratory of Medical Biochemistry and Clinical Analysis, Department of Bioanalysis, Faculty of Pharmaceutical Sciences (P-J.DS., E.G., A.V.), Department of Basic and Applied Medical Science, Faculty of Medicine and Health Sciences (P.D-C), Ghent University, Ghent, Belgium; Department of Pharmacy and Department of Pediatric Intensive Care, Ghent University Hospital, Ghent, Belgium (P.D-C.); and Certara UK Limited, Sheffield, United Kingdom (T.N.J., H.M.)., Gasthuys E; Laboratory of Medical Biochemistry and Clinical Analysis, Department of Bioanalysis, Faculty of Pharmaceutical Sciences (P-J.DS., E.G., A.V.), Department of Basic and Applied Medical Science, Faculty of Medicine and Health Sciences (P.D-C), Ghent University, Ghent, Belgium; Department of Pharmacy and Department of Pediatric Intensive Care, Ghent University Hospital, Ghent, Belgium (P.D-C.); and Certara UK Limited, Sheffield, United Kingdom (T.N.J., H.M.)., Vermeulen A; Laboratory of Medical Biochemistry and Clinical Analysis, Department of Bioanalysis, Faculty of Pharmaceutical Sciences (P-J.DS., E.G., A.V.), Department of Basic and Applied Medical Science, Faculty of Medicine and Health Sciences (P.D-C), Ghent University, Ghent, Belgium; Department of Pharmacy and Department of Pediatric Intensive Care, Ghent University Hospital, Ghent, Belgium (P.D-C.); and Certara UK Limited, Sheffield, United Kingdom (T.N.J., H.M.). |
| المصدر: | Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2023 Apr; Vol. 51 (4), pp. 499-508. Date of Electronic Publication: 2023 Jan 13. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics, etc.] Country of Publication: United States NLM ID: 9421550 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-009X (Electronic) Linking ISSN: 00909556 NLM ISO Abbreviation: Drug Metab Dispos Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Bethesda, Md., etc., American Society for Pharmacology and Experimental Therapeutics, etc.] |
| مواضيع طبية MeSH: | Models, Biological* , Monobactams*, Adult ; Humans ; Ceftazidime ; Anti-Bacterial Agents ; Muscles |
| مستخلص: | Physiologically based pharmacokinetic (PBPK) models consist of compartments representing different tissues. As most models are only verified based on plasma concentrations, it is unclear how reliable associated tissue profiles are. This study aimed to assess the accuracy of PBPK-predicted beta-lactam antibiotic concentrations in different tissues and assess the impact of using effect site concentrations for evaluation of target attainment. Adipose, bone, and muscle concentrations of five beta-lactams (piperacillin, cefazolin, cefuroxime, ceftazidime, and meropenem) in healthy adults were collected from literature and compared with PBPK predictions. Model performance was evaluated with average fold errors (AFEs) and absolute AFEs (AAFEs) between predicted and observed concentrations. In total, 26 studies were included, 14 of which reported total tissue concentrations and 12 unbound interstitial fluid (uISF) concentrations. Concurrent plasma concentrations, used as baseline verification of the models, were fairly accurate (AFE: 1.14, AAFE: 1.50). Predicted total tissue concentrations were less accurate (AFE: 0.68, AAFE: 1.89). A slight trend for underprediction was observed but none of the studies had AFE or AAFE values outside threefold. Similarly, predictions of microdialysis-derived uISF concentrations were less accurate than plasma concentration predictions (AFE: 1.52, AAFE: 2.32). uISF concentrations tended to be overpredicted and two studies had AFEs and AAFEs outside threefold. Pharmacodynamic simulations in our case showed only a limited impact of using uISF concentrations instead of unbound plasma concentrations on target attainment rates. The results of this study illustrate the limitations of current PBPK models to predict tissue concentrations and the associated need for more accurate models. SIGNIFICANCE STATEMENT: Clinical inaccessibility of local effect site concentrations precipitates a need for predictive methods for the estimation of tissue concentrations. This is the first study in which the accuracy of PBPK-predicted tissue concentrations of beta-lactam antibiotics in humans were assessed. Predicted tissue concentrations were found to be less accurate than concurrent predicted plasma concentrations. When using PBPK models to predict tissue concentrations, this potential relative loss of accuracy should be acknowledged when clinical tissue concentrations are unavailable to verify predictions. (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.) |
| المشرفين على المادة: | 0 (Monobactams) 9M416Z9QNR (Ceftazidime) 0 (Anti-Bacterial Agents) |
| تواريخ الأحداث: | Date Created: 20230113 Date Completed: 20230327 Latest Revision: 20230407 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1124/dmd.122.001129 |
| PMID: | 36639242 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1521-009X |
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| DOI: | 10.1124/dmd.122.001129 |