Performance Verification of CYP2C19 Enzyme Abundance Polymorphism Settings within the Simcyp Simulator v21.

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Computational Modeling in Pharmacology
• Enzyme Kinetics and Population Variability

Background:

• Physiologically based pharmacokinetic (PBPK) modeling is crucial for predicting drug-drug interactions (DDIs) in diverse populations.
• The Simcyp Simulator undergoes annual updates to incorporate new scientific findings and improve predictive accuracy.
• CYP2C19 enzyme abundance and phenotypes are key factors influencing drug metabolism and DDI outcomes.

Purpose of the Study:

• To verify updates to hepatic and intestinal CYP2C19 enzyme abundance in Simcyp Simulator version 21.
• To assess the impact of these updates on population clearance and DDI predictions.
• To evaluate the simulator's ability to predict pharmacokinetics of sensitive CYP2C19 substrates, omeprazole and lansoprazole.

Main Methods:

• Verification of Simcyp Simulator version 21 updates using omeprazole and lansoprazole clinical data.
• Assessment of area under the concentration-time curve (AUC) and Cmax recovery for each drug.
• Evaluation of victim DDI ratios and relative exposure between different CYP2C19 phenotypes.

Main Results:

• Simulated data met acceptance criteria for over 80% of omeprazole AUC values and over 80% of exposure ratios between phenotypes.
• Over 70% of lansoprazole AUC and Cmax values, and over 60% of DDI ratios, were within acceptance criteria.
• Omeprazole Cmax recovery was lower (50-70% within 2-fold), potentially due to formulation variability in the clinical dataset.

Conclusions:

• The updated CYP2C19 phenotype data in Simcyp Simulator version 21 reasonably describes the pharmacokinetics of omeprazole and lansoprazole.
• The simulator's performance supports its use for DDI assessment in polymorphic populations.
• Iterative refinement of PBPK models is essential for advancing drug interaction predictions.