Predictive Performance of Physiologically Based Pharmacokinetic (PBPK) Modeling of Drugs Extensively Metabolized by Major Cytochrome P450s in Children

Clin Pharmacol Ther. 2018 Jul;104(1):188-200. doi: 10.1002/cpt.905. Epub 2017 Nov 20.

Abstract

The accuracy of physiologically based pharmacokinetic (PBPK) model prediction in children, especially those younger than 2 years old, has not been systematically evaluated. The aim of this study was to characterize the pediatric predictive performance of the PBPK approach for 10 drugs extensively metabolized by CYP1A2 (theophylline), CYP2C8 (desloratidine, montelukast), CYP2C9 (diclofenac), CYP2C19 (esomeprazole, lansoprazole), CYP2D6 (tramadol), and CYP3A4 (itraconazole, ondansetron, sufentanil). Model performance in children was evaluated by comparing simulated plasma concentration-time profiles with observed clinical results for each drug and age group. PBPK models reasonably predicted the pharmacokinetics of desloratadine, diclofenac, itraconazole, lansoprazole, montelukast, ondansetron, sufentanil, theophylline, and tramadol across all age groups. Collectively, 58 out of 67 predictions were within 2-fold and 43 out of 67 predictions within 1.5-fold of observed values. Developed PBPK models can reasonably predict exposure in children age 1 month and older for an array of predominantly CYP metabolized drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / metabolism
  • Acetates / pharmacokinetics
  • Analgesics, Opioid / metabolism
  • Analgesics, Opioid / pharmacokinetics
  • Anti-Asthmatic Agents / metabolism
  • Anti-Asthmatic Agents / pharmacokinetics
  • Anti-Inflammatory Agents, Non-Steroidal / metabolism
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
  • Antifungal Agents / metabolism
  • Antifungal Agents / pharmacokinetics
  • Bronchodilator Agents / metabolism
  • Bronchodilator Agents / pharmacokinetics
  • Child
  • Child, Preschool
  • Cyclopropanes
  • Cytochrome P-450 CYP1A2 / metabolism
  • Cytochrome P-450 CYP2C19 / metabolism
  • Cytochrome P-450 CYP2C8 / metabolism
  • Cytochrome P-450 CYP2C9 / metabolism
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 Enzyme System / metabolism*
  • Diclofenac / metabolism
  • Diclofenac / pharmacokinetics
  • Esomeprazole / metabolism
  • Esomeprazole / pharmacokinetics
  • Histamine H1 Antagonists, Non-Sedating / metabolism
  • Histamine H1 Antagonists, Non-Sedating / pharmacokinetics
  • Humans
  • Infant
  • Infant, Newborn
  • Itraconazole / metabolism
  • Itraconazole / pharmacokinetics
  • Lansoprazole / metabolism
  • Lansoprazole / pharmacokinetics
  • Loratadine / analogs & derivatives
  • Loratadine / metabolism
  • Loratadine / pharmacokinetics
  • Models, Biological*
  • Ondansetron / metabolism
  • Ondansetron / pharmacokinetics
  • Pharmaceutical Preparations / metabolism*
  • Pharmacokinetics*
  • Proton Pump Inhibitors / metabolism
  • Proton Pump Inhibitors / pharmacokinetics
  • Quinolines / metabolism
  • Quinolines / pharmacokinetics
  • Serotonin Antagonists / metabolism
  • Serotonin Antagonists / pharmacokinetics
  • Sufentanil / metabolism
  • Sufentanil / pharmacokinetics
  • Sulfides
  • Theophylline / metabolism
  • Theophylline / pharmacokinetics
  • Tramadol / metabolism
  • Tramadol / pharmacokinetics

Substances

  • Acetates
  • Analgesics, Opioid
  • Anti-Asthmatic Agents
  • Anti-Inflammatory Agents, Non-Steroidal
  • Antifungal Agents
  • Bronchodilator Agents
  • Cyclopropanes
  • Histamine H1 Antagonists, Non-Sedating
  • Pharmaceutical Preparations
  • Proton Pump Inhibitors
  • Quinolines
  • Serotonin Antagonists
  • Sulfides
  • Lansoprazole
  • Diclofenac
  • Itraconazole
  • Tramadol
  • Ondansetron
  • Loratadine
  • Cytochrome P-450 Enzyme System
  • Sufentanil
  • Theophylline
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • CYP1A2 protein, human
  • CYP2C19 protein, human
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • desloratadine
  • montelukast
  • Esomeprazole