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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| Format: | Article |
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MDPI AG
2023-09-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/9/2348 |
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| author | Pieter-Jan De Sutter Phebe Rossignol Lien Breëns Elke Gasthuys An Vermeulen |
| author_facet | Pieter-Jan De Sutter Phebe Rossignol Lien Breëns Elke Gasthuys An Vermeulen |
| author_sort | Pieter-Jan De Sutter |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T22:15:06Z |
| format | Article |
| id | doaj.art-3287cb894b1b47cf9172ee031c0510b4 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T22:15:06Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-3287cb894b1b47cf9172ee031c0510b42023-11-19T12:28:32ZengMDPI AGPharmaceutics1999-49232023-09-01159234810.3390/pharmaceutics15092348Predicting Volume of Distribution in Neonates: Performance of Physiologically Based Pharmacokinetic ModellingPieter-Jan De Sutter0Phebe Rossignol1Lien Breëns2Elke Gasthuys3An Vermeulen4Department of Bioanalysis, Ghent University, 9000 Ghent, BelgiumDepartment of Bioanalysis, Ghent University, 9000 Ghent, BelgiumDepartment of Bioanalysis, Ghent University, 9000 Ghent, BelgiumDepartment of Bioanalysis, Ghent University, 9000 Ghent, BelgiumDepartment of Bioanalysis, Ghent University, 9000 Ghent, BelgiumThe 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.https://www.mdpi.com/1999-4923/15/9/2348physiologically based pharmacokinetics (PBPK)pharmacokineticsneonatesvolume of distributionallometric scalingdevelopmental pharmacology |
| spellingShingle | Pieter-Jan De Sutter Phebe Rossignol Lien Breëns Elke Gasthuys An Vermeulen Predicting Volume of Distribution in Neonates: Performance of Physiologically Based Pharmacokinetic Modelling Pharmaceutics physiologically based pharmacokinetics (PBPK) pharmacokinetics neonates volume of distribution allometric scaling developmental pharmacology |
| 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 | physiologically based pharmacokinetics (PBPK) pharmacokinetics neonates volume of distribution allometric scaling developmental pharmacology |
| url | https://www.mdpi.com/1999-4923/15/9/2348 |
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