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 (and C ) 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 (and C ) 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.

In vitro–in vivo correlation of the drug–drug interaction potential of antiretroviral HIV treatment regimens on CYP1A1 substrate riociguat

“…a variable content of CYP1A1 in hepatocytes including the rather unlikely lower limit of f m,CYP1A1 = 0.0. Focusing on the inhibitory potency on CYP3A4 in hepatocytes using midazolam as a sensitive CYP3A4 substrate, results of this study revealed that the significant decrease in clearance of midazolam with fixed-dose antiretroviral combinations containing strong CYP3A4 inhibitors cobicistat, ritonavir, atazanavir, and darunavir, as well as clarithromycin, and ketoconazole is consistent with previous clinical studies (Table S7) [16,[58][59][60][61]. Based on the published clinical literature [16], no DDIs were expected with CYP3A substrates for abacavir/dolutegravir/lamivudine (components of TRIUMEQ ® ) or emtricitabine/rilpivirine/tenofovir disoproxil (components of COMPLERA ® ), which is consistent with the in vitro data observed with recombinant CYP3A4 and in human hepatocytes using midazolam as a substrate in the present study.…”

Implementation of a Physiologically Based Pharmacokinetic Modeling Approach to Guide Optimal Dosing Regimens for Imatinib and Potential Drug Interactions in Paediatrics

“…The default PBPK models for carbamazepine, ketoconazole, and rifampicin in Simcyp Simulator were used (Almond et al, 2016;Liu et al, 2017). The predictive performance of the PBPK models in paediatric population need to be verified prior to their further use, since the original models were developed in adults.…”

“…The induction of CYP3A and CYP2C8 was modeled by an increase in protein synthesis (turnover) rate constant in hepatocytes and enterocytes according to an enzyme turnover model (Almond et al, 2016). Ketoconazole inhibits CYP3A4 and CYP2C8 competitively with an inhibitory constant (Ki u ) of 15 nmol/L (Liu et al, 2017) and 2.2 μmol/L, respectively. PBPK simulations were carried out with n = 50 (40% of female) for each age band.…”

Theoretical consideration of the properties of intestinal flow models on route‐dependent drug removal: Segregated Flow (SFM) vs. Traditional (TM)

“…Interests on intestinal versus liver metabolism have been increasing. The intestine is seriously being considered in physiologically‐based pharmacokinetic (PBPK) modeling (Badhan, Penny, Galetin, & Houston, ; Cong, Doherty, & Pang, ; Dressman, Thelen, & Jantratid, ; Fenneteau, Poulin, & Nekka, ; Guo et al, ; Liu et al, ; Mano, Sugiyama, & Ito, ; Pang, ; Parrott & Lavé, ; Zhang et al, ), especially for drug metabolism, drug transport and drug–drug interactions (Chen et al, ; Duan, Zhao, & Zhang, ; Marzolini et al, ; Yoshikado et al, ). In some rarely documented instances, intestinally formed metabolites have been found to be inhibitors of liver metabolism (Quinney et al, ), causing changes in protein (enzyme or transporter) contents in mechanism‐based inhibition, MBI (Guo et al, ; Moj et al, ; Quinney et al, ; Rowland Yeo et al, ; Zhang et al, ).…”

“…Since the intestine is divided into three segmental regions (duodenum, jejunum, and ileum), catenary models that incorporate sequential processing of drugs within the segments have evolved for consideration of the different sites of absorption and metabolism (Agoram, Woltosz, & Bolger, 2001;Bolger, Lukacova, & Woltosz, 2009;Tam, Tirona, & Pang, 2003;Yu & Amidon, 1999;Yu, Lipka, Crison, & Amidon, 1996). The popularized advanced dissolution absorption metabolism (ADAM) Liu et al, 2017;Rowland Yeo, Jamei, Yang, Tucker, & Rostami-Hodjegan, 2010) and advanced compartmental absorption and transition (ACAT) (Bolger et al, 2009;Daga, Bolger, Haworth, Clark, & Martin, 2018;Hens & Bolger, 2019) models are based on these principles, emphasizing the use of the drug physicochemical properties and drug permeability on drug absorption and disposition. Interests on intestinal versus liver metabolism have been increasing.…”