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- 01GRKFD573R1V4PASZW2REZ62Y classification C3.
- 01GRKFD573R1V4PASZW2REZ62Y date "2022".
- 01GRKFD573R1V4PASZW2REZ62Y language "eng".
- 01GRKFD573R1V4PASZW2REZ62Y type conference.
- 01GRKFD573R1V4PASZW2REZ62Y subject "Biology and Life Sciences".
- 01GRKFD573R1V4PASZW2REZ62Y presentedAt urn:uuid:83b22e2b-b467-4ddb-98cd-3b273be2f338.
- 01GRKFD573R1V4PASZW2REZ62Y abstract "A key perceived benefit of physiologically based pharmacokinetic (PBPK) modelling is its ability to predict drug concentrations in tissue. The equations for estimating these local concentrations were mainly developed based on animal tissue concentration data and the validity of tissue predictions in humans is therefore less clear. The primary aim of this work was therefore to compare PBPK model predictions with clinically observed tissue concentrations for a selection of beta-lactam antibiotics (piperacillin cefazoline, cefuroxime, ceftazidime and meropenem) in perfusion limited tissues (adipose, bone and muscle). A literature search was performed to identify studies reporting both plasma and tissue concentrations (total concentrations in tissue homogenate or concentrations in microdialysate) of each of the selected beta-lactam antibiotics in relatively healthy adults. From these studies, PK profiles in plasma and tissue were extracted and compared with PBPK simulations. The PBPK substrate models used were drawn from published reports or developed and validated using healthy volunteer data (piperacillin). PBPK modelling was done using Simcyp® V20. Tissue-to-plasma coefficients were predicted using the Rodgers & Rowland equations for total tissue (homogenate) concentrations. Unbound extracellular (microdialysate) tissue concentrations were simulated by equating the tissue-to-plasma coefficient to the free fraction in plasma. Observed concentrations, time to maximum concentration in tissue and tissue-to-plasma coefficients were quantitatively compared to PBPK-based predictions to assess model performance. Plasma profile predictions were fairly accurate with on average 85% of the concentrations within twofold of the predicted values. Tissue predictions were in general less accurate (average of 61% within twofold), but no overall trend for under- or overprediction could be discerned. As expected, tissue concentrations based on homogenates underestimated the unbound concentration in the extracellular space, since beta-lactam antibiotics hardly distribute intracellularly. Time to maximum tissue concentrations could not be reliably compared due to sparse sampling at the start of dosing interval. Predicted tissue-to-plasma coefficients were within twofold of observed values for 59% of studies. These results show that PBPK models developed and validated for predicting plasma concentrations might fail in accurately predicting concentrations in perfusion limited tissues.".
- 01GRKFD573R1V4PASZW2REZ62Y author 00D24390-F0EE-11E1-A9DE-61C894A0A6B4.
- 01GRKFD573R1V4PASZW2REZ62Y author 11556A76-F0EE-11E1-A9DE-61C894A0A6B4.
- 01GRKFD573R1V4PASZW2REZ62Y author 7340E12A-2AE5-11E3-A4E0-796A10BDE39D.
- 01GRKFD573R1V4PASZW2REZ62Y author 7764B038-1DB5-11E4-941E-5C49B5D1D7B1.
- 01GRKFD573R1V4PASZW2REZ62Y dateCreated "2023-02-06T13:42:19Z".
- 01GRKFD573R1V4PASZW2REZ62Y dateModified "2024-07-09T07:45:35Z".
- 01GRKFD573R1V4PASZW2REZ62Y name "Physiologically based pharmacokinetic models for the prediction of beta-lactam antibiotic concentrations in perfusion-limited tissues".
- 01GRKFD573R1V4PASZW2REZ62Y sameAs LU-01GRKFD573R1V4PASZW2REZ62Y.
- 01GRKFD573R1V4PASZW2REZ62Y sourceOrganization urn:uuid:612bd706-5796-4fe5-9a1f-30131fe170ae.
- 01GRKFD573R1V4PASZW2REZ62Y sourceOrganization urn:uuid:8a006909-db5c-4f82-94c2-271c9d3f84cc.
- 01GRKFD573R1V4PASZW2REZ62Y type C3.