Analyzing parametric influences driving age-associated changes in absorption using a PBPK-GSA approach.

Area of Science:

• Pharmacokinetics and Drug Development
• Geriatric Pharmacology
• Computational Modeling

Background:

• Older adults face higher risks of adverse drug effects due to altered pharmacokinetics, particularly absorption.
• Limited data and high variability complicate understanding drug absorption changes in the elderly.
• Physiologically based pharmacokinetic (PBPK) models offer advantages for studying special populations like the elderly.

Purpose of the Study:

• To integrate global sensitivity analysis with PBPK models to characterize age-associated absorption changes.
• To evaluate the impact of age-related absorption variability on drug pharmacokinetics.
• To improve risk assessment for oral drug dosing in advanced age populations.

Main Methods:

• Physiologically based pharmacokinetic (PBPK) models were developed using PK-Sim®.
• Global sensitivity analysis, specifically the Elementary Effects (Morris) method, was implemented in R.
• Three drugs from Biopharmaceutical Classification System classes I-III were tested against three age-associated hypotheses.

Main Results:

• Successfully integrated global sensitivity analysis with PBPK models for age-related absorption.
• Demonstrated the utility of the Morris method for assessing parametric interactions in PBPK models.
• Quantified the impact of age-associated absorption changes on drug pharmacokinetics for selected drugs.

Conclusions:

• Global sensitivity analysis provides a robust method for PBPK model risk assessment in special populations.
• This integrated approach enhances the characterization of age-related pharmacokinetic variability.
• Improved PBPK modeling can better predict and mitigate drug-related risks in older adults.