Physiologically Based Pharmacokinetic Modeling of Monoclonal Antibodies in Pediatric Populations Using PK-Sim
Physiologically based pharmacokinetic (PBPK) models are increasingly used to support pediatric dose selection for small molecule drugs. In contrast, only a few pediatric PBPK models for therapeutic antibodies have been published recently, and the knowledge on the maturation of the processes relevant...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-06-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2020.00868/full |
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| author | Sumit Basu Yi Ting (Kayla) Lien Valvanera Vozmediano Jan-Frederik Schlender Thomas Eissing Stephan Schmidt Christoph Niederalt |
| author_facet | Sumit Basu Yi Ting (Kayla) Lien Valvanera Vozmediano Jan-Frederik Schlender Thomas Eissing Stephan Schmidt Christoph Niederalt |
| author_sort | Sumit Basu |
| collection | DOAJ |
| description | Physiologically based pharmacokinetic (PBPK) models are increasingly used to support pediatric dose selection for small molecule drugs. In contrast, only a few pediatric PBPK models for therapeutic antibodies have been published recently, and the knowledge on the maturation of the processes relevant for antibody pharmacokinetics (PK) is limited compared to small molecules. The aim of this study was, thus, to evaluate predictions from antibody PBPK models for children which were scaled from PBPK models for adults in order to identify respective knowledge gaps. For this, we used the generic PBPK model implemented in PK-Sim without further modifications. Focusing on general clearance and distribution mechanisms, we selected palivizumab and bevacizumab as examples for this evaluation since they show simple, linear PK which is not governed by drug-specific target mediated disposition at usual therapeutic dosages, and their PK has been studied in pediatric populations after intravenous application. The evaluation showed that the PK of palivizumab was overall reasonably well predicted, while the clearance for bevacizumab seems to be underestimated. Without implementing additional ontogeny for antibody PK-specific processes into the PBPK model, bodyweight normalized clearance increases only moderately in young children compared to adults. If growth during aging at the time of the simulation was considered, the apparent clearance is approximately 20% higher compared to simulations for which growth was not considered for newborns due to the long half-life of antibodies. To fully understand the differences and similarities in the PK of antibodies between adults and children, further research is needed. By integrating available information and data, PBPK modeling can contribute to reveal the relevance of involved processes as well as to generate and test hypothesis. |
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| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T10:24:51Z |
| publishDate | 2020-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-288902e7c998413bb6490a1f965d1cd02022-12-22T02:50:20ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122020-06-011110.3389/fphar.2020.00868507426Physiologically Based Pharmacokinetic Modeling of Monoclonal Antibodies in Pediatric Populations Using PK-SimSumit Basu0Yi Ting (Kayla) Lien1Valvanera Vozmediano2Jan-Frederik Schlender3Thomas Eissing4Stephan Schmidt5Christoph Niederalt6Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, United StatesCenter for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, United StatesCenter for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, United StatesClinical Pharmacometrics, Bayer AG, Leverkusen, GermanyClinical Pharmacometrics, Bayer AG, Leverkusen, GermanyCenter for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, United StatesClinical Pharmacometrics, Bayer AG, Leverkusen, GermanyPhysiologically based pharmacokinetic (PBPK) models are increasingly used to support pediatric dose selection for small molecule drugs. In contrast, only a few pediatric PBPK models for therapeutic antibodies have been published recently, and the knowledge on the maturation of the processes relevant for antibody pharmacokinetics (PK) is limited compared to small molecules. The aim of this study was, thus, to evaluate predictions from antibody PBPK models for children which were scaled from PBPK models for adults in order to identify respective knowledge gaps. For this, we used the generic PBPK model implemented in PK-Sim without further modifications. Focusing on general clearance and distribution mechanisms, we selected palivizumab and bevacizumab as examples for this evaluation since they show simple, linear PK which is not governed by drug-specific target mediated disposition at usual therapeutic dosages, and their PK has been studied in pediatric populations after intravenous application. The evaluation showed that the PK of palivizumab was overall reasonably well predicted, while the clearance for bevacizumab seems to be underestimated. Without implementing additional ontogeny for antibody PK-specific processes into the PBPK model, bodyweight normalized clearance increases only moderately in young children compared to adults. If growth during aging at the time of the simulation was considered, the apparent clearance is approximately 20% higher compared to simulations for which growth was not considered for newborns due to the long half-life of antibodies. To fully understand the differences and similarities in the PK of antibodies between adults and children, further research is needed. By integrating available information and data, PBPK modeling can contribute to reveal the relevance of involved processes as well as to generate and test hypothesis.https://www.frontiersin.org/article/10.3389/fphar.2020.00868/fullphysiologically based pharmacokinetic (PBPK) modelingPK-Simmonoclonal antibodiespediatricschildren |
| spellingShingle | Sumit Basu Yi Ting (Kayla) Lien Valvanera Vozmediano Jan-Frederik Schlender Thomas Eissing Stephan Schmidt Christoph Niederalt Physiologically Based Pharmacokinetic Modeling of Monoclonal Antibodies in Pediatric Populations Using PK-Sim Frontiers in Pharmacology physiologically based pharmacokinetic (PBPK) modeling PK-Sim monoclonal antibodies pediatrics children |
| title | Physiologically Based Pharmacokinetic Modeling of Monoclonal Antibodies in Pediatric Populations Using PK-Sim |
| title_full | Physiologically Based Pharmacokinetic Modeling of Monoclonal Antibodies in Pediatric Populations Using PK-Sim |
| title_fullStr | Physiologically Based Pharmacokinetic Modeling of Monoclonal Antibodies in Pediatric Populations Using PK-Sim |
| title_full_unstemmed | Physiologically Based Pharmacokinetic Modeling of Monoclonal Antibodies in Pediatric Populations Using PK-Sim |
| title_short | Physiologically Based Pharmacokinetic Modeling of Monoclonal Antibodies in Pediatric Populations Using PK-Sim |
| title_sort | physiologically based pharmacokinetic modeling of monoclonal antibodies in pediatric populations using pk sim |
| topic | physiologically based pharmacokinetic (PBPK) modeling PK-Sim monoclonal antibodies pediatrics children |
| url | https://www.frontiersin.org/article/10.3389/fphar.2020.00868/full |
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