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Development and applications of a physiologically-based model of paediatric oral drug absorption
T N Johnson1, J J Bonner1, G T Tucker2
1Simcyp Limited (a Certara company), Sheffield, UK.
Insights
This study developed a physiologically-based model for paediatric drug absorption, finding slower absorption but consistent bioavailability for some drugs in neonates. Further data is needed to refine models for pediatric oral formulations.
Area of Science:
- Pharmacokinetics and Biopharmaceutics
- Pediatric Drug Development
- Physiologically-Based Pharmacokinetic (PBPK) Modeling
Background:
- Growing interest in pediatric drug absorption and oral formulation development for neonates, infants, and children.
- Need for advanced biopharmaceutics tools tailored to the unique physiology of pediatric populations.
- Limited availability of age-specific data for gastrointestinal tract parameters in children.
Purpose of the Study:
- To develop and apply a physiologically-based model for predicting drug absorption in pediatric patients from birth onwards.
- To integrate pediatric age-specific parameters into a dissolution, absorption, and metabolism model within a PBPK platform.
- To assess the model's performance by simulating the oral absorption of key drugs across various pediatric ages.
Main Methods:
- Development of a physiologically-based model incorporating pediatric age-specific parameters (salivary flow, gastric pH, gastric emptying, bile salt concentrations).
- Integration of algorithms into a dissolution, absorption, and metabolism model within a PBPK platform.
- Simulation of oral drug absorption for theophylline, paracetamol (BCS class 1), and ketoconazole (BCS class 2) in pediatric age groups.
Main Results:
- Model predicted slower oral absorption (median tmax 3h vs 2h) but invariant fraction absorbed (fa) for theophylline and paracetamol in early neonates compared to older children.
- Predicted tmax for ketoconazole was similar in neonates and adults (~1h), but with a higher fraction absorbed (fa) in neonates (0.87 vs 0.69).
- Simulations align with existing clinical observations regarding pediatric drug absorption characteristics.
Conclusions:
- The developed physiologically-based model provides a valuable tool for understanding and predicting pediatric drug absorption.
- Expansion of the model with emerging data on gastrointestinal tract ontogeny is necessary for improved accuracy.
- Further validation against in vivo data is crucial to confirm age-related changes in oral drug absorption in pediatric populations.
Abstract:
There is increasing interest in paediatric drug absorption and the development of biopharmaceutics tools to facilitate the development of oral formulations for neonates, infants and children. We describe the development and application of a physiologically-based model of paediatric drug absorption applicable from full term birth onwards. Paediatric age-specific parameters were included for salivary flow, gastric pH, gastric emptying (and associated food effects) and duodenal bile salt concentrations and the associated algorithms were integrated into a dissolution, absorption and metabolism model as part of a PBPK platform. For other parameters, there was either evidence for no age-related changes or a lack of data, so that adult values were applied. An initial assessment of the model was carried out by simulating the oral absorption of theophylline, paracetamol and ketoconazole over a range of paediatric ages. The absorption of the first two drugs, both BCS class 1 compounds, was predicted to be slower in early neonates compared to older age groups (median tmax values of 3 vs 2h, respectively), but with invariant fraction absorbed (fa). This is in agreement with clinical observations. The tmax of ketoconazole, a BCS class 2 compound, was predicted to be about 1h in both neonates and adults, but the fa value was higher in the former (0.87 vs 0.69). There is clearly a need to expand the components of the model as new information on the ontogeny of GI tract parameters becomes available, and to assess it against more in vivo data with evidence of specific age-related changes in oral drug absorption.
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