Abstract
PurposeChanges 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.MethodsPharmacokinetic (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.ResultsThe 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%).ConclusionIn 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.
Highlights
Changes in drug absorption and first-pass metabolism have been reported throughout the pediatric age range
With cytochrome P450 (CYP) being an enzyme family involved in metabolism of many drugs [5], this study focuses on CYP3A enzymes, as they are abundant in both intestine and liver [6,7]
For intercompartmental clearance of midazolam to the first peripheral compartment, body weight was found as a covariate, while no covariate was identified for intercompartmental clearance to the second peripheral compartment
Summary
Changes in drug absorption and first-pass metabolism have been reported throughout the pediatric age range. 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. In order to distinguish between intestinal and hepatic clearance (and their maturation), a combination of mechanistic and empirical models can be useful, as was shown in adults before [13,14] This hybrid of approaches seems necessary as for full physiologically-based PK models in children not all parameters are always available and/or identifiable, while empirical models may lack direct physiological interpretation. The latter is problematic, because both hepatic and intestinal metabolism contribute to first-pass metabolism. The combination of PBPK concepts with population modelling using PK data from children enables incorporation of prior knowledge of the system, while obtaining more insight into the system by parameter estimation based on reverse translation of the observed clinical data [15]
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