Quantitative Evaluation of Pharmacokinetic Inhibition of CYP3A Substrates by Ketoconazole: A Simulation Study

Abstract

The US Food and Drug Administration draft drug interaction guidance recommends that 400 mg ketoconazole (KTZ) be administered once daily for several days (QD400) for maximal CYP3A inhibition. Some investigators suggest that a single dose of 400 mg (SD400) KTZ is sufficient given its short half-life (t(1/2) approximately 3-5 hr). To determine the impact of KTZ regimens on CYP3A inhibition, we simulated AUC fold-change (AUCR) in the presence of SD400, QD400, or 200 mg twice-daily (BID200) KTZ for theoretical CYP3A substrates. Ratios of AUCR (AUCR(QD400)/AUCR(SD400) and AUCR(BID200) AUCR(QD400)) increase with increasing bioavailability and increasing substrate t(1/2). The SD400 KTZ regimen may provide maximal inhibition only for a subset of substrates (ie, low bioavailability and short t(1/2)). For substrates with t(1/2) longer than that of KTZ, multiple KTZ dosing is critical and BID200 appears to provide greater inhibition than QD400. Also, timing of KTZ administration should be optimized to allow maximal presystemic enzyme inhibition prior to substrate administration.

Simulation of Clinical Drug-Drug Interactions from Hepatocyte CYP3A4 Induction Data and Its Potential Utility in Trial Designs

“…In recent studies, Simcyp has been successfully applied by various investigators to quantitatively predict metabolism-based DDIs (Einolf, 2007;Fahmi et al, 2009). It was also used to evaluate the impact of various dosing regimens of ketoconazole on the extent of CYP3A inhibition (Zhao et al, 2009).…”

Optimization of Drug-Drug Interaction Study Design: Comparison of Minimal Physiologically Based Pharmacokinetic Models on Prediction of CYP3A Inhibition by Ketoconazole

“…To estimate the contribution of CYP3A enzymes to systemic clearance and bioavailability, ketoconazole is often used, despite a number of frequently acknowledged drawbacks to this approach (Ohno et al, 2007;Zhao et al, 2009). The most prominent shortcoming of ketoconazole as the preferred in vivo strong inhibitor of CYP3A is the poor understanding of the determinants of inhibition in whole cells and at the enzyme site.…”

Clinical CYP3A Inhibitor Alternatives to Ketoconazole, Clarithromycin and Itraconazole, Are Not Transported into the Liver by Hepatic Organic Anion Transporting Polypeptides and Organic Cation Transporter 1

“…High-dose ketoconazole (400 mg by mouth, each day for $5 days) has long been the gold-standard cytochrome P450 3A (CYP3A) inhibitor in clinical drug-drug interaction (DDI) studies (Zhao et al, 2009). In 2013, based on emerging clinical safety reports, both the US Food and Drug Administration and European Medicines Agency advised against using ketoconazole in DDI studies (http://www.fda.gov/Drugs/DrugSafety/ ucm371017.htm).…”

“…Ketoconazole has been favored due to nearly complete CYP3A inhibition in humans at clinically relevant doses, selectivity, and predictability of DDIs based on unbound plasma concentrations (Zhao et al, 2009;Han et al, 2013). The ability to predict DDIs based on unbound circulating exposures is of particular practical importance.…”

“…The ability to predict DDIs based on unbound circulating exposures is of particular practical importance. Steady-state ketoconazole concentrations available for interaction with hepatic CYP3A enzyme are in equilibrium with plasma unbound concentrations because of ketoconazole's high passive membrane permeability (Clarysse et al, 2009) and absence of carrier-facilitated hepatic uptake (Zhao et al, 2009). As such, ketoconazole DDIs are accurately predicted by circulating concentrations corrected for plasma protein binding (Smith et al, 2010), which are easily sampled, unlike intracellular unbound liver concentrations which are practically impossible to sample directly in humans.…”