Sampling Site Has a Critical Impact on Physiologically Based Pharmacokinetic Modeling

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Computational Biology and Bioinformatics
• Translational Pharmacology

Background:

• Physiologically based pharmacokinetic (PBPK) models typically simulate drug concentrations in the central venous compartment (e.g., right atrium).
• Clinical pharmacokinetic studies often measure drug concentrations from peripheral veins (e.g., arm vein), leading to potential discrepancies.
• This difference in sampling sites can impact the accuracy of PBPK model evaluations and predictions.

Purpose of the Study:

• To develop and verify a physiologically based peripheral forearm sampling site model for PBPK simulations.
• To investigate the impact of sampling site selection on PBPK model outputs and parameter optimization.
• To ensure meaningful comparison between simulated and observed peripheral venous drug concentrations.

Main Methods:

• Development of a physiologically based peripheral forearm sampling site model.
• Verification of the model using pharmacokinetic data for nicotine, ketamine, lidocaine, and fentanyl.
• Investigation of the generalized effect of sampling site on PBPK simulation outputs, including Cmax and Tmax.
• Analysis of metabolite profiles from central versus peripheral sampling sites.

Main Results:

• Significant concentration discrepancies were observed between central and peripheral venous simulations for drugs with large volumes of distribution.
• Differences in Cmax and Tmax were noted, impacting pharmacokinetic parameter estimation.
• Simulated central venous metabolite profiles differed from those observed in peripheral veins.
• Using the incorrect sampling site in PBPK models led to biased evaluations and erroneous parameter optimization for fentanyl.

Conclusions:

• The choice of sampling site in PBPK models is critical and must align with clinical data collection methods.
• Failure to match sampling sites can lead to clinically significant errors in pharmacokinetic predictions, affecting drug safety and efficacy assessments.
• The developed peripheral sampling site model enables accurate simulation of arm vein drug concentrations for improved PBPK model evaluation and application.