Characterization of Intestinal and Hepatic CYP3A-Mediated Metabolism of Midazolam in Children Using a Physiological Population Pharmacokinetic Modelling Approach

• Published in: Pharmaceutical research 2018-09, Vol.35 (9), p.182-13, Article 182
• Main Authors: Brussee, Janneke M., Yu, Huixin, Krekels, Elke H. J., Palić, Semra, Brill, Margreke J. E., Barrett, Jeffrey S., Rostami-Hodjegan, Amin, de Wildt, Saskia N., Knibbe, Catherijne A. J.
• Format: Article
• Language: English
• Subjects: absorption; Adolescent; Age; Algorithms; Anesthetics, Intravenous - metabolism; Anesthetics, Intravenous - pharmacokinetics; Bioavailability; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Body weight; Child; Child, Preschool; Children; CYP3A; Cytochrome P-450 CYP3A - metabolism; Digestive system; Drug metabolism; extraction ratio; Female; first-pass metabolism; Gastrointestinal tract; gut wall; Humans; Infant; Intestinal Mucosa - metabolism; Intestine; Liver; Liver - metabolism; Male; Medical Law; Metabolism; Midazolam; Midazolam - metabolism; Midazolam - pharmacokinetics; Models, Biological; Oral administration; pediatrics; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Physiological aspects; Physiology; Research Paper; Standard error; Target marketing
• ISSN: 0724-8741; 1573-904X; 1573-904X
• DOI: 10.1007/s11095-018-2458-6

Purpose Changes in drug absorption and first-pass metabolism have been reported throughout the pediatric age range. Our aim is to characterize both intestinal and hepatic CYP3A-mediated metabolism of midazolam in children in order to predict first-pass and systemic metabolism of CYP3A substrates. Methods Pharmacokinetic (PK) data of midazolam and 1-OH-midazolam from 264 post-operative children 1–18 years of age after oral administration were analyzed using a physiological population PK modelling approach. In the model, consisting of physiological compartments representing the gastro-intestinal tract and liver,intrinsic intestinal and hepatic clearances were estimated to derive values for bioavailability and plasma clearance. Results The whole-organ intrinsic clearance in the gut wall and liver were found to increase with body weight, with a 105 (95% confidence interval (CI): 5–405) times lower intrinsic gut wall clearance than the intrinsic hepatic clearance (i.e. 5.08 L/h (relative standard error (RSE) 10%) versus 527 L/h (RSE 7%) for a 16 kg individual, respectively). When expressed per gram of organ, intrinsic clearance increases with increasing body weight in the gut wall, but decreases in the liver, indicating that CYP3A-mediated intrinsic clearance and local bioavailability in the gut wall and liver do not change with age in parallel. The resulting total bioavailability was found to be age-independent with a median of 20.8% in children (95%CI: 3.8–50.0%). Conclusion In conclusion, the intrinsic CYP3A-mediated gut wall clearance is substantially lower than the intrinsic hepatic CYP3A-mediated clearance in children from 1 to 18 years of age, and contributes less to the overall first-pass metabolism compared to adults.