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

Abstract：

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.

journal_name

Pharm Res

journal_title

Pharmaceutical research

authors

Brussee JM,Yu H,Krekels EHJ,Palić S,Brill MJE,Barrett JS,Rostami-Hodjegan A,de Wildt SN,Knibbe CAJ

doi

10.1007/s11095-018-2458-6

subject

Has Abstract

pub_date

2018-07-30 00:00:00

pages

182

issue

9

eissn

0724-8741

issn

1573-904X

pii

10.1007/s11095-018-2458-6

journal_volume

35

pub_type

杂志文章

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