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Bioavailability Considerations in Evaluating Drug‐Drug Interactions Using the Population Pharmacokinetic Approach
Author(s) -
Duan John Z.,
Jackson Andre J.,
Zhao Ping
Publication year - 2011
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010377200
Subject(s) - pharmacokinetics , bioavailability , ketoconazole , population , volume of distribution , pharmacology , midazolam , drug , drug drug interaction , cyp3a , drug interaction , drug metabolism , covariate , population pharmacokinetics , medicine , chemistry , metabolism , mathematics , statistics , cytochrome p450 , environmental health , dermatology , sedation , antifungal
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.