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Bioavailability Considerations in Evaluating Drug‐Drug Interactions Using the Population Pharmacokinetic Approach

Applying a comedication (COMD) covariate to apparent clearance (CLapp = CL/F) is a common practice when using population pharmacokinetics (PopPK) to study metabolism‐based drug‐drug interactions (DDI). This study evaluates the importance of independently applying COMD to F and CL to account for DDI at the level of first‐pass metabolism. A known DDI between single oral doses of the CYP3A substrate midazolam (5 mg) and the inhibitor ketoconazole (400 mg) was simulated using a physiologically based pharmacokinetic simulator SimCyp in virtual subjects. The simulated midazolam data were analyzed by PopPK method under the following scenarios by applying COMD effect to (1) CLapp only, (2) CL and F, and (3) CLapp and apparent volume of distribution (Vapp = V/F), assuming V is unchanged.