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- Title
Development and Verification of a Japanese Pediatric Physiologically Based Pharmacokinetic Model with Emphasis on Drugs Eliminated by Cytochrome P450 or Renal Excretion.
- Authors
Johnson, Trevor N.; Abduljalil, Khaled; Pan, Xian; Emoto, Chie
- Abstract
Physiologically based pharmacokinetic (PBPK) models are useful in bridging drug exposure in different ethnic groups, and there is increasing regulatory application of this approach in adults. Reported pediatric PBPK models tend to focus on the North European population, with few examples in other ethnic groups. This study describes the development and verification of a Japanese pediatric PBPK population. The development of the model was based on the existing North European pediatric population. Japanese systems and clinical data were collated from public databases and the literature, and the underlying demographics and equations were optimized so that physiological outputs represented the Japanese pediatric population. The model was tested using 14 different small molecule drugs, eliminated by a variety of pathways, including cytochrome P450 3A4 (CYP3A4) metabolism and renal excretion. Given the limitations of the clinical data, the overall performance of the model was good, with 44/62 predictions for PK parameters (area under the plasma drug concentration–time curve, AUC; maximum serum concentration, Cmax; clearance, CL) being within 0.8‐ to 1.25‐fold, 56/62 within 0.67‐ to 1.5‐fold, and 61/62 within 0.5‐ to 2.0‐fold of the observed values. Specific results for the 5 CYP3A4 substrates showed 20/31 cases were predicted within 0.8‐ to 1.25‐fold, 27/31 within 0.67‐ to 1.5‐fold, and all were within 0.5‐ to 2.0‐fold of the observed values. Given the increased regulatory use of pediatric PBPK in drug development, expanding these models to other ethnic groups are important. Considering qualifying these models based on the context of use, there is a need to expand on the current research to include a larger range of drugs with different elimination pathways. Collaboration among academic, industry, model providers, and regulators will facilitate further development.
- Subjects
JAPAN; BIOLOGICAL models; COMPUTER simulation; BIOCHEMISTRY; CYTOCHROME P-450; METABOLIC clearance rate; PEDIATRICS; DRUG design; DRUG interactions; DESCRIPTIVE statistics; OXIDOREDUCTASES; DRUG development
- Publication
Journal of Clinical Pharmacology, 2023, Vol 63, Issue 10, p1156
- ISSN
0091-2700
- Publication type
Article
- DOI
10.1002/jcph.2317