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Predicting Volume of Distribution in Neonates: Performance of Physiologically Based Pharmacokinetic Modelling

The volume of distribution at steady state (Vss) in neonates is still often estimated through isometric scaling from adult values, disregarding developmental changes beyond body weight. This study aimed to compare the accuracy of two physiologically based pharmacokinetic (PBPK) Vss prediction method...

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Autores principales: De Sutter, Pieter-Jan, Rossignol, Phebe, Breëns, Lien, Gasthuys, Elke, Vermeulen, An
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10536587/
https://www.ncbi.nlm.nih.gov/pubmed/37765316
http://dx.doi.org/10.3390/pharmaceutics15092348
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author De Sutter, Pieter-Jan
Rossignol, Phebe
Breëns, Lien
Gasthuys, Elke
Vermeulen, An
author_facet De Sutter, Pieter-Jan
Rossignol, Phebe
Breëns, Lien
Gasthuys, Elke
Vermeulen, An
author_sort De Sutter, Pieter-Jan
collection PubMed
description The volume of distribution at steady state (Vss) in neonates is still often estimated through isometric scaling from adult values, disregarding developmental changes beyond body weight. This study aimed to compare the accuracy of two physiologically based pharmacokinetic (PBPK) Vss prediction methods in neonates (Poulin & Theil with Berezhkovskiy correction (P&T+) and Rodgers & Rowland (R&R)) with isometrical scaling. PBPK models were developed for 24 drugs using in-vitro and in-silico data. Simulations were done in Simcyp (V22) using predefined populations. Clinical data from 86 studies in neonates (including preterms) were used for comparison, and accuracy was assessed using (absolute) average fold errors ((A)AFEs). Isometric scaling resulted in underestimated Vss values in neonates (AFE: 0.61), and both PBPK methods reduced the magnitude of underprediction (AFE: 0.82–0.83). The P&T+ method demonstrated superior overall accuracy compared to isometric scaling (AAFE of 1.68 and 1.77, respectively), while the R&R method exhibited lower overall accuracy (AAFE: 2.03). Drug characteristics (LogP and ionization type) and inclusion of preterm neonates did not significantly impact the magnitude of error associated with isometric scaling or PBPK modeling. These results highlight both the limitations and the applicability of PBPK methods for the prediction of Vss in the absence of clinical data.
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spelling pubmed-105365872023-09-29 Predicting Volume of Distribution in Neonates: Performance of Physiologically Based Pharmacokinetic Modelling De Sutter, Pieter-Jan Rossignol, Phebe Breëns, Lien Gasthuys, Elke Vermeulen, An Pharmaceutics Article The volume of distribution at steady state (Vss) in neonates is still often estimated through isometric scaling from adult values, disregarding developmental changes beyond body weight. This study aimed to compare the accuracy of two physiologically based pharmacokinetic (PBPK) Vss prediction methods in neonates (Poulin & Theil with Berezhkovskiy correction (P&T+) and Rodgers & Rowland (R&R)) with isometrical scaling. PBPK models were developed for 24 drugs using in-vitro and in-silico data. Simulations were done in Simcyp (V22) using predefined populations. Clinical data from 86 studies in neonates (including preterms) were used for comparison, and accuracy was assessed using (absolute) average fold errors ((A)AFEs). Isometric scaling resulted in underestimated Vss values in neonates (AFE: 0.61), and both PBPK methods reduced the magnitude of underprediction (AFE: 0.82–0.83). The P&T+ method demonstrated superior overall accuracy compared to isometric scaling (AAFE of 1.68 and 1.77, respectively), while the R&R method exhibited lower overall accuracy (AAFE: 2.03). Drug characteristics (LogP and ionization type) and inclusion of preterm neonates did not significantly impact the magnitude of error associated with isometric scaling or PBPK modeling. These results highlight both the limitations and the applicability of PBPK methods for the prediction of Vss in the absence of clinical data. MDPI 2023-09-19 /pmc/articles/PMC10536587/ /pubmed/37765316 http://dx.doi.org/10.3390/pharmaceutics15092348 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
De Sutter, Pieter-Jan
Rossignol, Phebe
Breëns, Lien
Gasthuys, Elke
Vermeulen, An
Predicting Volume of Distribution in Neonates: Performance of Physiologically Based Pharmacokinetic Modelling
title Predicting Volume of Distribution in Neonates: Performance of Physiologically Based Pharmacokinetic Modelling
title_full Predicting Volume of Distribution in Neonates: Performance of Physiologically Based Pharmacokinetic Modelling
title_fullStr Predicting Volume of Distribution in Neonates: Performance of Physiologically Based Pharmacokinetic Modelling
title_full_unstemmed Predicting Volume of Distribution in Neonates: Performance of Physiologically Based Pharmacokinetic Modelling
title_short Predicting Volume of Distribution in Neonates: Performance of Physiologically Based Pharmacokinetic Modelling
title_sort predicting volume of distribution in neonates: performance of physiologically based pharmacokinetic modelling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10536587/
https://www.ncbi.nlm.nih.gov/pubmed/37765316
http://dx.doi.org/10.3390/pharmaceutics15092348
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