Cytochrome P450 3A-mediated first-pass and systemic drug metabolism in children
From descriptive to physiological models that can predict oral absorption and elimination of CYP3A substrates across the pediatric age range.
- Catherijne Knibbe
Children are not just small adults. Age-related physiological changes in children result in altered pharmacokinetic (PK) profiles of drugs. Among the metabolizing enzymes, cytochrome P450 (CYP) 3A enzymes play a major role in both drug absorption and metabolism through local activity in the intestines and the liver. Midazolam is mainly metabolized by CYP3A and a well-known probe drug for this CYP3A enzyme system.
The aim of this PhD project is to predict CYP3A-mediated oral absorption and metabolism of CYP3A substrates in children using semi-physiological PK modelling. In this project, age-related changes in midazolam metabolism are studied across the pediatric age range. There is specific emphasis on physiological factors affecting CYP3A-mediated metabolism such as inflammation and organ failure beyond changes due to growth and development. Both oral absorption and first-pass metabolism of midazolam are characterized using a (semi-)physiological population modelling approach. This approach uses the statistical power of the population approach, while it takes into account key principles from physiology like blood flow and ontogeny of enzyme activity. Ultimately, we aim to predict the maturation of CYP3A in the intestine and liver across the pediatric population using a (semi-) physiological PK model for midazolam and possibly other CYP3A substrates.