| _version_ | 1866901723241512960 |
|---|---|
| author | Macente, Julia Nauwelaerts, Nina Van Neste, Martje Huang, Miao-Chan allegaert, karel Smits, Anne Huys, Isabelle Annaert, Pieter |
| author_facet | Macente, Julia Nauwelaerts, Nina Van Neste, Martje Huang, Miao-Chan allegaert, karel Smits, Anne Huys, Isabelle Annaert, Pieter |
| contents | <p><strong>Introduction</strong>: Several pathologies require pharmacotherapy during infancy and childhood. Generating information regarding use and safety during early life is relevant for the development and labelling of drugs used in this population. However, knowledge of the physiology and pharmacokinetics in this population is still limited since the maturational physiology and ontogeny need to be considered. A promising tool to predict drug concentrations in the infant population is physiologically-based pharmacokinetic (PBPK) modelling and simulation. Work Package 3 (WP3) of ConcePTION aims to generate a non-clinical testing platform to determine drug transfer into human milk, and subsequent exposure of infants.<span> </span></p> <p><strong>Aim</strong>: The aim of this deliverable is to report the development and qualification of the infant PBPK models using Simcyp® and PK-Sim® software to predict the plasma concentration time profile of amoxicillin, levetiracetam and valproic acid.<span> </span></p> <p><strong>Methods</strong>: The PBPK models were developed in Simcyp® V21 (Certara, L.P., Sheffield, UK) and in PK-Sim® V9.1 (Open Systems Pharmacology) for amoxicillin, levetiracetam and valproic acid. First, a PBPK model was developed for adult healthy volunteers and qualified against <em>in vivo </em>clinical data. In a second step, the qualified adult PBPK models were extrapolated to infants by accounting for the physiological changes, ontogeny functions and values regarding the age dependency of anthropometrics. Clinical data from literature were collected for infants aged from 3 months to 1 year old and used for model development and qualification purposes.<span> </span></p> <p><strong>Results</strong>: The adult PBPK models developed in Simcyp® and PK-Sim® for the three model drugs adequately described the observed plasma concentration time profiles, as well the PK parameters (<em>i.e., </em>Cmax and AUC) in adult healthy volunteers. The infant PBPK models in both software platforms showed a good prediction of the pharmacokinetic parameters and were able to adequately capture the plasma concentration-time profiles when comparted to the clinical data.<span> </span></p> <p><strong>Conclusion</strong>: The presented PBPK models adequately describe the plasma PK of amoxicillin, valproic acid and levetiracetam in adults and infants. Integration of the qualified infant models with the corresponding lactation PBPK models, as previously developed using both software platforms, will result in a comprehensive maternal-infant PBPK model, allowing the simulation of systemic exposure to maternal medication in breastfed infants <em>via </em>human milk.<span> </span></p> |
| format | Recurso digital |
| id | zenodo_https___doi_org_10_5281_zenodo_18416167 |
| institution | Zenodo |
| language | |
| publishDate | 2023 |
| publisher | Zenodo |
| record_format | zenodo |
| spellingShingle | Individual PBPK model for predicting exposure of infants to selected drugs (D3.8) Macente, Julia Nauwelaerts, Nina Van Neste, Martje Huang, Miao-Chan allegaert, karel Smits, Anne Huys, Isabelle Annaert, Pieter <p><strong>Introduction</strong>: Several pathologies require pharmacotherapy during infancy and childhood. Generating information regarding use and safety during early life is relevant for the development and labelling of drugs used in this population. However, knowledge of the physiology and pharmacokinetics in this population is still limited since the maturational physiology and ontogeny need to be considered. A promising tool to predict drug concentrations in the infant population is physiologically-based pharmacokinetic (PBPK) modelling and simulation. Work Package 3 (WP3) of ConcePTION aims to generate a non-clinical testing platform to determine drug transfer into human milk, and subsequent exposure of infants.<span> </span></p> <p><strong>Aim</strong>: The aim of this deliverable is to report the development and qualification of the infant PBPK models using Simcyp® and PK-Sim® software to predict the plasma concentration time profile of amoxicillin, levetiracetam and valproic acid.<span> </span></p> <p><strong>Methods</strong>: The PBPK models were developed in Simcyp® V21 (Certara, L.P., Sheffield, UK) and in PK-Sim® V9.1 (Open Systems Pharmacology) for amoxicillin, levetiracetam and valproic acid. First, a PBPK model was developed for adult healthy volunteers and qualified against <em>in vivo </em>clinical data. In a second step, the qualified adult PBPK models were extrapolated to infants by accounting for the physiological changes, ontogeny functions and values regarding the age dependency of anthropometrics. Clinical data from literature were collected for infants aged from 3 months to 1 year old and used for model development and qualification purposes.<span> </span></p> <p><strong>Results</strong>: The adult PBPK models developed in Simcyp® and PK-Sim® for the three model drugs adequately described the observed plasma concentration time profiles, as well the PK parameters (<em>i.e., </em>Cmax and AUC) in adult healthy volunteers. The infant PBPK models in both software platforms showed a good prediction of the pharmacokinetic parameters and were able to adequately capture the plasma concentration-time profiles when comparted to the clinical data.<span> </span></p> <p><strong>Conclusion</strong>: The presented PBPK models adequately describe the plasma PK of amoxicillin, valproic acid and levetiracetam in adults and infants. Integration of the qualified infant models with the corresponding lactation PBPK models, as previously developed using both software platforms, will result in a comprehensive maternal-infant PBPK model, allowing the simulation of systemic exposure to maternal medication in breastfed infants <em>via </em>human milk.<span> </span></p> |
| title | Individual PBPK model for predicting exposure of infants to selected drugs (D3.8) |
| url | https://doi.org/10.5281/zenodo.18416167 |