2021 FDA Science Forum
An In Vitro Model Simulating Gastro-Intestinal Digestion in Neonates and Young Infants (2 Months Old or Younger) and Findings with Study Test Model Drugs: Furosemide, Fluconazole and Ibuprofen
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Contributing OfficeCenter for Drug Evaluation and Research
Abstract
Background
The coining of “therapeutic or pharmaceutical orphans” by Harry Shirkey initiated dedicated efforts, regulations and research to advance drug development for pediatric patients. Due to the inherent complexities of conducting studies in pediatric patients, an in vitro modeling approach is described here for providing knowledge to support design of informed and targeted in vivo study(ies) for pediatric patients.
Purpose
To assess the performance of the developed in vitro gastrointestinal (GI) digestion model and explore factors that may influence in vitro and in vivo solubilization (i.e., bio-accessibility) of drug substances in neonates and young infants.
Methodology
The dynamic in vitro lipolysis model (Klitgaard et al. 2017) was used for testing study model drugs (furosemide, ibuprofen and fluconazole). Their solubilization and phase distribution were studied in various media (e.g., infant formula, and fed and fasted state simulated gastric and intestinal biorelevant media with and without digestive enzymes) with varying viscosity.
Results
Furosemide: Displayed higher solubilization in the aqueous phase in fed state than “fasted state” (i.e., pre-feeding). Furosemide solubilization as drug substance or crushed tablet increased in the presence of food (infant formula) but was not further influenced by the GI digestion of the infant formula. Ibuprofen: All drug was solubilized in the aqueous phase of the gastric and intestinal steps in fed state experiments. However, in “fasted state” experiments, in the gastric step, ibuprofen precipitated completely and redissolved in the intestinal step where 40% of ibuprofen was solubilized in the aqueous phase. Digestion products decreased the amount of ibuprofen in the aqueous phase, as ibuprofen partitioned between the lipid and the aqueous phase. Fluconazole was fully solubilized in the aqueous phase in both gastric and intestinal steps and was unaffected by the altered test conditions.
Conclusions
The developed GI digestion model may inform in vitro drug product performance by mimicking feeding patterns and processes occurring in the GI tract of the neonates and young infants. Integration of such knowledge with intended therapeutic outcomes can advance building in clinical relevance in development of dosage forms for neonates and young infants with greater therapeutic benefit, and ultimately, facilitate better informed regulatory decision-making.
