CYP3A4-based drug–drug interaction: CYP3A4 substrates’ pharmacokinetic properties and ketoconazole dose regimen effect

Abstract

The aim of the study was to assess the magnitude of the CYP3A4 inhibitory effect of 2 dosing regimens of ketoconazole and the influence of the pharmacokinetic properties of the CYP3A4 substrate on the extent of the substrate exposure increase. For this purpose, a clinical study was conducted and PBPK modeling simulations were performed. A crossover study was conducted in healthy subjects. The study was designed to compare the effects of different regimens of reversible CYP3A4 inhibitors, i.e., ketoconazole 400 mg OD, ketoconazole 200 mg BID, on two CYP3A4 substrates, alprazolam and midazolam, reflecting different pharmacokinetic properties in terms of first-pass effect and elimination. In parallel, time-based simulations were performed using the Simcyp population-based Simulator to address the usefulness of modeling to assess interaction clinical study design with CYP3A4 substrates. Comparison of the OD versus BID regimens for ketoconazole showed an opposite trend for the 2 substrates: BID (200 mg) dosing regimen provided the maximal clearance inhibition for alprazolam, while it was OD (400 mg) dosing regimen for midazolam. However, these effects are moderate despite the well-known pharmacokinetic differences between these substrates, suggesting that these differences are not enough. In the other way round, these investigations show how two CYP3A4 substrates can be different without leading to a major impact of the ketoconazole dosing regimen. The clinical findings are consistent with the Simcyp predictions, in particular the opposite trend observed with midazolam and alprazolam and the ketoconazole dosing regimen. These clinical investigations showed the influence of the CYP3A4 substrates' pharmacokinetic properties and the relevance of ketoconazole dose regimen on the magnitude of the interaction ratios. In addition, PBPK Simcyp simulations demonstrated how they can be used to help clinical study design assessment to capture the maximum effect.

Mechanisms and Clinical Significance of Pharmacokinetic-Based Drug-Drug Interactions with Drugs Approved by the U.S. Food and Drug Administration in 2017

“…The differential effects of ketoconazole on the PK of abemaciclib in comparison with other strong CYP3A inhibitors may be due to several factors, including the nonlinearity of the AUC versus [I]/K i relationship between 90% and 100% inhibition (Ito et al, 2004) and/or the differential effects of strong inhibitors on first-pass versus systemic CYP3A metabolism of abemaciclib (Boxenbaum, 1999). Similar behavior has been observed with midazolam, the sensitive substrate of CYP3A, where coadministration with ketoconazole (400 mg once daily for 5 days) increased midazolam AUC approximately 17-fold (Boulenc et al, 2016), whereas itraconazole (200 mg once daily for 4 days) and clarithromycin (500 mg twice daily for 7 days) resulted in relatively smaller increases (10.80-and 8.39fold, respectively) (Olkkola et al, 1994;Gurley et al, 2006). Given the large magnitude of exposure change in abemaciclib when coadministered with ketoconazole and the potential concerns for unknown offtarget toxicities related to increased abemaciclib exposure, concomitant use of ketoconazole with abemaciclib should be avoided.…”

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

“…The studies were approved by the Ethics Committee of the Medical Faculty of Eskişehir Osmangazi University, Turkey. All subjects were in good health as indicated by medical history, physical [1,2,[4][5][6][7][8][9][10][11] examination and biochemical tests. The subjects were asked to abstain from alcohol and xanthinecontaining beverages during the studies.…”

“…Mean plasma concentrations of ketoconazole measured after oral doses of (A) 200 and (B) 400 mg in published studies …”

Verification of a physiologically based pharmacokinetic model of ritonavir to estimate drug–drug interaction potential of CYP3A4 substrates

“…The health authority warnings and recommendations limit the use of ketoconazole as an antifungal treatment or a model CYP3A4 inhibitor in clinical DDI studies and prompted a search for appropriate alternatives (Boulenc et al, ; Fahmi et al, ). Itraconazole, clarithromycin and ritonavir have been proposed as replacements.…”