Akademik Veri Yönetim Sistemi
BIOPHARMACEUTICS & DRUG DISPOSITION, cilt.38, sa.3, ss.260-270, 2017 (SCI-Expanded)
The impact of different single oral doses of ketoconazole (KTZ) (100, 200 and 400mg) and of staggering its dosage (400mg at -12, -2, 0, 2 and 4h), with respect to the administration of a single 5mg 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 C-max) 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 C-max) 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 (C) 2016 John Wiley & Sons, Ltd.