PMID- 37496106
OWN - NLM
STAT- MEDLINE
DCOM- 20230911
LR  - 20230911
IS  - 1552-4604 (Electronic)
IS  - 0091-2700 (Linking)
VI  - 63
IP  - 10
DP  - 2023 Oct
TI  - Development and Verification of a Japanese Pediatric Physiologically Based 
      Pharmacokinetic Model with Emphasis on Drugs Eliminated by Cytochrome P450 or 
      Renal Excretion.
PG  - 1156-1168
LID - 10.1002/jcph.2317 [doi]
AB  - 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, C(max) ; 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.
CI  - (c) 2023, The American College of Clinical Pharmacology.
FAU - Johnson, Trevor N
AU  - Johnson TN
AD  - Simcyp Division, Certara UK Limited, Sheffield, UK.
FAU - Abduljalil, Khaled
AU  - Abduljalil K
AUID- ORCID: 0000-0003-0725-9237
AD  - Simcyp Division, Certara UK Limited, Sheffield, UK.
FAU - Pan, Xian
AU  - Pan X
AD  - Simcyp Division, Certara UK Limited, Sheffield, UK.
FAU - Emoto, Chie
AU  - Emoto C
AD  - Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical 
      University, Tokyo, Japan.
AD  - Translational Research Division, Chugai Pharmaceutical Co., Ltd, Tokyo, Japan.
LA  - eng
PT  - Journal Article
DEP - 20230808
PL  - England
TA  - J Clin Pharmacol
JT  - Journal of clinical pharmacology
JID - 0366372
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
SB  - IM
MH  - Child
MH  - Humans
MH  - Computer Simulation
MH  - *Cytochrome P-450 CYP3A/metabolism
MH  - Cytochrome P-450 Enzyme System/metabolism
MH  - Drug Interactions
MH  - East Asian People
MH  - Models, Biological
MH  - *Renal Elimination
OTO - NOTNLM
OT  - Japanese
OT  - PBPK modeling
OT  - model verification
OT  - ontogeny
OT  - pediatrics
EDAT- 2023/07/27 01:09
MHDA- 2023/09/11 06:42
CRDT- 2023/07/26 23:47
PHST- 2023/05/02 00:00 [received]
PHST- 2023/07/23 00:00 [accepted]
PHST- 2023/09/11 06:42 [medline]
PHST- 2023/07/27 01:09 [pubmed]
PHST- 2023/07/26 23:47 [entrez]
AID - 10.1002/jcph.2317 [doi]
PST - ppublish
SO  - J Clin Pharmacol. 2023 Oct;63(10):1156-1168. doi: 10.1002/jcph.2317. Epub 2023 
      Aug 8.