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Clinical Trial
. 2010 Oct;88(4):499-505.
doi: 10.1038/clpt.2010.119. Epub 2010 Aug 25.

Accurate prediction of dose-dependent CYP3A4 inhibition by itraconazole and its metabolites from in vitro inhibition data

I Templeton  1 , C-C Peng, K E Thummel, C Davis, K L Kunze, N Isoherranen
Affiliations
Clinical Trial

Accurate prediction of dose-dependent CYP3A4 inhibition by itraconazole and its metabolites from in vitro inhibition data

I Templeton et al. Clin Pharmacol Ther. 2010 Oct.

Abstract

Inhibitory drug metabolites may contribute to drug-drug interactions (DDIs). The aim of this study was to determine the importance of inhibitory metabolites of itraconazole (ITZ) in in vivo cytochrome P450 (CYP) 3A4 inhibition. The pharmacokinetics of ITZ and midazolam (MDZ) were determined in six healthy volunteers in four sessions after administration of MDZ with and without oral ITZ. After doses of 50, 200, and 400 mg of ITZ, the clearance of orally administered MDZ decreased by 27, 74, and 83%, respectively. The in vivo half maximal inhibitory concentration (IC(50)) for ITZ ranged from 5 to 132 nmol/l in the six subjects. The metabolites of ITZ were estimated to account for ~50% of the total CYP3A4 inhibition, with the relative contribution increasing with time after ITZ dosing. Of the total of 18 interactions observed, 15 (84%) could be predicted within a twofold error margin, with improved accuracy observed when ITZ metabolites were included in the predictions. This study shows that the metabolites of ITZ contribute to CYP3A4 inhibition and need to be accounted for in quantitative rationalization of ITZ-mediated DDIs.

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Figures

Figure 1
Figure 1
Effect of escalating doses of itraconazole (ITZ) on disposition of oral midazolam (MDZ). Panel a shows the plasma concentration–time curves for midazolam in the control session and three ITZ sessions. MDZ was administered 4 h after the oral dose of ITZ. Panel b depicts the AUC values of MDZ in the six study subjects, in the control session and in the sessions involving escalating doses of ITZ.
Figure 2
Figure 2
In vivo inhibitory potency (IC50 values) for itraconazole (ITZ) in the six study subjects. The subjects are labeled “S” along with a study number, and the fitted IC50 value is given in the inset of each panel. The maximum percent inhibition is shown as the Emax value in the insets.
Figure 3
Figure 3
Predicted vs. observed interactions between itraconazole (ITZ) and midazolam after escalating doses of ITZ. The circles represent data from each individual subject after a 50-mg dose of ITZ; the boxes represent the data from each subject after the 200-mg dose; and the triangles represent the data from each subject after the 400-mg dose. Each interaction was predicted using the measured unbound concentrations of either (a) ITZ alone, or (b) ITZ and its metabolites. The unbound IC50 values were measured in human liver microsomes. AUC, area under the curve.
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