A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam

Area of Science:

• Pharmacology
• Pharmacokinetics
• Pediatric Drug Development

Background:

• Physiologically based pharmacokinetic (PBPK) models are increasingly important in pediatric drug development.
• Recent FDA recommendations highlight the need for robust PBPK models in this area.

Purpose of the Study:

• To demonstrate the development of a pediatric PBPK model using existing adult drug data.
• To establish age-specific dose requirements for lorazepam in children (0-18 years).

Main Methods:

• A population-PBPK model for lorazepam was created using PK-Sim v4.2.
• The model was scaled for pediatric physiology, including tissue composition and maturation of elimination processes.
• Simulations were performed to determine pediatric dose requirements based on targeted adult exposures.

Main Results:

• Pediatric dose requirements (mg/kg) for young children (1-3 years) exceeded adult levels on a weight-adjusted basis.
• The PBPK model achieved good predictive accuracy for plasma concentrations (73% within 1.5-fold error).
• Predictions for clearance and volume of distribution showed acceptable accuracy compared to observed pediatric data.

Conclusions:

• The developed PBPK model effectively estimates lorazepam pharmacokinetics in children across different ages.
• This workflow provides a valuable tool for pediatric drug development and dose optimization.
• The model supports informed decision-making for pediatric dosing regimens.