title: Bioavailability considerations in evaluating drug-drug interactions using the population pharmacokinetic approach.
abstract: Applying a comedication (COMD) covariate to apparent clearance (CL(app) = 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) CL(app) only, (2) CL and F, and (3) CL(app) and apparent volume of distribution (V(app) = V/F), assuming V is unchanged. The mean simulated degree of interaction, measured by midazolam AUC ratio with and without ketoconazole (AUCR), was 10.28. Scenario 1 underestimated AUCR. When COMD was independently applied to F and V(app) in scenarios 2 and 3, lower objective function values of the PopPK analysis and more accurate AUCR estimates were achieved. AUCR estimates were also dependent on sampling. The authors conclude that when significant inhibition of the first-pass metabolism of the substrate is anticipated, COMD effects should be applied to both CL and F in PopPK analysis.
authors.affiliation: FDA/CDER/OPS/ONDQA, WO Bldg 21 Room 1616, 10903 New Hampshire Ave, Silver Spring, MD 20993, USA. john.duan@fda.hhs.gov
authors.forename: John Z
authors.initials: JZ
authors.lastname: Duan
authors.forename: Andre J
authors.initials: AJ
authors.lastname: Jackson
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
mesh_terms: D000465:Algorithms; D001682:Biological Availability; D001711:Biotransformation; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics; D008954:Models, Biological; D010599:Pharmacokinetics
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D007654:Ketoconazole