title: The absorption kinetics of ketoconazole plays a major role in explaining the reported variability in the level of interaction with midazolam: Interplay between formulation and inhibition of gut wall and liver metabolism.
abstract: The impact of different single oral doses of ketoconazole (KTZ) (100, 200 and 400 mg) and of staggering its dosage (400 mg at -12, -2, 0, 2 and 4 h), with respect to the administration of a single 5 mg oral dose of midazolam (MDZ) on the extent of inhibition of the metabolism of the latter, was evaluated in healthy subjects in two separate studies. Escalation of the ketoconazole dosage resulted in 2.3 (1.9), 2.7 (1.7) and 4.2 (2.5) -fold increases in the mean AUC(0,12h)(and Cmax) values of midazolam. Dose-staggering was associated with 3.9 (2.5), 4.9 (2.9), 5.4 (2.8), 2.0 (1.3) and 1.2 (0.9) -fold increases in the mean AUC(0,12h)(and Cmax) of midazolam. These findings could be predicted by physiologically based pharmacokinetic (PBPK) modelling using the ADAM (advanced dissolution absorption and metabolism) model within the Simcyp Simulator (Version 12 Release 2) to characterize the absorption kinetics of ketoconazole with respect to disintegration time, supersaturation ratio and precipitation rate. This study also emphasizes a need to account for inter-individual variability in the gut wall and systemic exposure of inhibitors with physicochemical properties similar to ketoconazole, in particular in their rate of oral absorption and when using different pharmaceutical formulations, in designing and evaluating the extent of drug-drug interactions. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Simcyp Ltd, Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.affiliation: Simcyp Ltd, Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK.
authors.forename: H Kim
authors.initials: HK
authors.lastname: Crewe
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey.
authors.forename: Mahmut
authors.initials: M
authors.lastname: Ozdemir
authors.affiliation: Simcyp Ltd, Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Rowland Yeo
authors.affiliation: Department of Human Metabolism (Emeritus), Medicine and Biomedical Sciences, University of Sheffield, Sheffield, S10 2JF, UK.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Tucker
authors.affiliation: Simcyp Ltd, Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK.|Manchester Pharmacy School, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Amin
authors.identifier: http://orcid.org/0000-0003-3917-844X
authors.initials: A
authors.lastname: Rostami-Hodjegan
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D041981:Gastrointestinal Tract / Q000378:metabolism*; D006801:Humans; D007654:Ketoconazole / Q000097:blood / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D008954:Models, Biological
chemical_list: D008874:Midazolam; D007654:Ketoconazole
keywords: DDI; Ketoconazole; absorption; inter-individual variability; midazolam