Bioavailability considerations in evaluating drug-drug interactions using the population pharmacokinetic approach

Area of Science:

• Pharmacokinetics
• Drug Metabolism
• Computational Biology

Background:

• Population pharmacokinetics (PopPK) commonly uses comedication (COMD) covariates on apparent clearance (CL(app)) to model drug-drug interactions (DDIs).
• This approach may not fully capture DDIs affecting first-pass metabolism.

Purpose of the Study:

• To evaluate the impact of independently applying COMD covariates to bioavailability (F) and clearance (CL) for improved DDI assessment.
• To determine the optimal covariate application strategy in PopPK for first-pass metabolism DDIs.

Main Methods:

• Simulated a known DDI between midazolam (CYP3A substrate) and ketoconazole (inhibitor) using a physiologically based pharmacokinetic simulator (SimCyp).
• Analyzed simulated midazolam data using PopPK under three scenarios: COMD on CL(app) only, COMD on CL and F, and COMD on CL(app) and apparent volume of distribution (V(app)).

Main Results:

• The simulated midazolam AUC ratio (AUCR) was 10.28.
• Applying COMD to CL(app) alone underestimated the AUCR.
• Independent application of COMD to F and V(app) (Scenarios 2 and 3) yielded lower objective function values and more accurate AUCR estimates.
• AUCR estimates were sensitive to sampling strategies.

Conclusions:

• When significant inhibition of first-pass metabolism is expected, COMD effects should be applied to both CL and F in PopPK analyses.
• This strategy enhances the accuracy of DDI modeling and prediction.