ArticlePharmaceutical research2018
Characterization of Intestinal and Hepatic CYP3A-Mediated Metabolism of Midazolam in Children Using a Physiological Population Pharmacokinetic Modelling Approach.
Article in Pharmaceutical research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 32 citations in OpenAlex.
- Midazolam premedication: shaping pediatric perioperative outcomes.Journal of anesthesia · 2026Article
- Single-Agent Sedation for Behavioral Management in Pediatric Dentistry: An Umbrella Review of Agents, Routes of Administration, Providers, and Clinical Settings.Children (Basel, Switzerland) · 2026Review
- Population Physiologically-Based Pharmacokinetic Modeling to Determine Ontogeny: A Quantitative Clinical Pharmacology Example in Pediatric Rare Disease.CPT: pharmacometrics & systems pharmacology · 2026Review
- Prediction of Pharmacokinetics for CYP3A4-Metabolized Drugs in Pediatrics and Geriatrics Using Dynamic Age-Dependent Physiologically Based Pharmacokinetic Models.Pharmaceutics · 2025Article
- Combining data on the bioavailability of midazolam and physiologically-based pharmacokinetic modeling to investigate intestinal CYP3A4 ontogeny.CPT: pharmacometrics & systems pharmacology · 2024Article
- Challenges of pediatric pharmacotherapy: A narrative review of pharmacokinetics, pharmacodynamics, and pharmacogenetics.European journal of clinical pharmacology · 2024Review
- Pharmacokinetic-Pharmacodynamic Modeling of Midazolam in Pediatric Surgery.Pharmaceutics · 2023Article
- Quantitative analysis of gastrointestinal fluid absorption and secretion to estimate luminal fluid dynamics in rats.Scientific reports · 2023Article
- Estimation of FMO3 Ontogeny by Mechanistic Population Pharmacokinetic Modelling of Risdiplam and Its Impact on Drug-Drug Interactions in Children.Clinical pharmacokinetics · 2023Article
- Influence of Age and Sex on the Pharmacokinetics of Midazolam and the Depth of Sedation in Pediatric Patients Undergoing Minor Surgeries.Pharmaceutics · 2023Article
- Sex and Age Influence on Association ofDiagnostics (Basel, Switzerland) · 2022Article
- Innovative approaches and recent advances in the study of ontogeny of drug metabolism and transport.British journal of clinical pharmacology · 2022Review
- Pharmacokinetics and Metabolism of Ziritaxestat (GLPG1690) in Healthy Male Volunteers Following Intravenous and Oral Administration.Clinical pharmacology in drug development · 2022Article
- Age-Related Changes in Pediatric Physiology: Quantitative Analysis of Organ Weights and Blood Flows : Age-Related Changes in Pediatric Physiology.The AAPS journal · 2021Article
- The Oral Bioavailability and Metabolism of Midazolam in Stable Critically Ill Children: A Pharmacokinetic Microtracing Study.Clinical pharmacology and therapeutics · 2021Article
- Composite midazolam and 1'-OH midazolam population pharmacokinetic model for constitutive, inhibited and induced CYP3A activity.Journal of pharmacokinetics and pharmacodynamics · 2020Article
- Pharmacokinetics in children with chronic kidney disease.Pediatric nephrology (Berlin, Germany) · 2020Review
Corrections and comments
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Authors and funding
9 authors at 7 institutions in 5 countries.
Funding
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.
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