The effect of ingestion time interval on the interaction between itraconazole and triazolam

Neuvonen, Pertti J.; Varhe, Anu; Olkkola, Klaus T.

doi:10.1016/s0009-9236(96)90059-4

Cited by 47 publications

(25 citation statements)

References 15 publications

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“…It is expected that if MDZ is administered at the time point of t max of ITZ, a greater effect on F g and F h will be observed than with a dose-staggered design. However, in a study that investigated the effect of ingestion time interval on the interaction between ITZ and triazolam, a larger magnitude of inhibition was observed when ITZ and triazolam doses were separated by 3 or 12 h as compared with administering them simultaneously,12 thereby suggesting that ITZ causes a persistent inhibition of CYP3A4, perhaps because of its circulating metabolites. Unfortunately, in these studies involving dose staggering and timing of administration, the concentrations of the circulating metabolites were not available, and therefore the relative contributions of the metabolites cannot be characterized.…”

Section: Discussionmentioning

confidence: 99%

Accurate Prediction of Dose-Dependent CYP3A4 Inhibition by Itraconazole and Its Metabolites From In Vitro Inhibition Data

Templeton

Peng

Thummel

et al. 2010

Clin Pharmacol Ther

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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.Many clinically important cytochrome P450 (CYP) inhibitors have been shown to possess circulating metabolites, 1 and many of these metabolites are predicted to contribute to in vivo drug-drug interactions (DDIs). 2 Classic examples of inhibitors with circulating inhibitory metabolites include three potent CYP inhibitors: itraconazole (ITZ),3 fluoxetine,4 and bupropion.5 Norfluoxetine, the primary circulating metabolite of fluoxetine, has been shown to be responsible for the persistent CYP2D6 inhibition after administration of fluoxetine,6 although no quantitative prediction of CYP2D6 inhibition by norfluoxetine as compared with fluoxetine was shown. Using atomoxetine as an example, quantitative predictions of the contribution of metabolites to in vivo DDIs were performed, and, despite the overall weak in vivo inhibition of CYP3A4 and CYP2D6 by atomoxetine, the metabolites were predicted to be mainly responsible for the interaction. 7 The metabolites of ITZ have been predicted to account for ~50% of the overall CYP3A4 inhibition in vivo. This prediction is based on in vivo disposition data of ITZ and its three NIH Public Access RESULTSSix healthy volunteers (one woman and five men), in the age range of 22-42 (mean 34) years and within 20% of optimal body mass index, completed the study. An additional female subject was enrolled, but she withdrew after the midazolam (MDZ) control session because of nausea and vomiting. No other side effects or possible adverse effects were observed in any of the subjects. All subjects had normal liver and kidney function and were in good health. Each subject was homozygous for CYP3A5*3 and hence was expected to lack expression of functional CYP3A5 protein. Individuals with potential CYP3A5 expression based on genotype were excluded from the study because CYP3A5 has been shown not to metabolize ITZ. 3 MDZ pharmacokinetics were measured after escalati...

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Section: Discussionmentioning

confidence: 99%

Accurate Prediction of Dose-Dependent CYP3A4 Inhibition by Itraconazole and Its Metabolites From In Vitro Inhibition Data

Templeton

Peng

Thummel

et al. 2010

Clin Pharmacol Ther

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“…Of interest to note was the ability of the MDM method to simulate DDI of trials using different dosing regimens. In the itraconazole-triazolam trial of Neuvonen et al (1996), itraconazole was dosed simultaneously with triazolam or 3, 12, or 24 h before treatment with triazolam (Table VI). It is evident that the [I]/K i and MSM approaches could not predict the magnitude differences of the interaction as well as the MDM, even accounting for the [I] differences reported in Neuvonen et al Although the version of Simcyp used for the MDM approach here could not account for inhibitory metabolites of itraconazole (evidenced by the sustained DDI effect in the actual trial), later versions of the model simulate kinetics of inhibitory metabolites from in vitro metabolism data and incorporate them in the predictions of any DDI.…”

Section: Cyp3amentioning

confidence: 99%

Comparison of different approaches to predict metabolic drug-drug interactions

Einolf

2007

TXEN

120

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Three approaches were compared to predict the actual magnitude of drug interaction (the mean fold-change in the area under the curve (AUC)) of reversible or irreversible (mechanism-based) cytochrome P450 (CYP) inhibitors. These were: (1) the pragmatic use of the '[I]/K(i)' approach; (2) the 'Mechanistic-Static Model' (MSM), which is a more complex extension of the '[I]/K(i)' approach that incorporates f(m,CYP), intestinal availability for CYP3A substrates, and mechanism-based inhibition (MBI); and (3) the 'Mechanistic-Dynamic Model' (MDM) which considers the time-variant change in the concentration of the inhibitor by using physiologically-based pharmacokinetic (PBPK) models (as implemented within the Simcyp(R) Population-Based ADME Simulator). The three approaches ([I]/K(i), MSM, and MDM) predicted a 'correct' drug-drug interaction (DDI) result (interaction: Greater than or equal to twofold; no interaction: Less than twofold) in 74, 87, and 80% of the 100 trials evaluated, respectively. Importantly, for trials with a greater than or equal to twofold change in AUC in the presence of the inhibitor (59 trials), the [I]/K(i), MSM, and MDM approaches predicted the mean AUC change within twofold of actual in 17, 53, and 64% of the trials, respectively. Overall, the MDM approach showed an improvement in the prediction of DDI magnitude compared to the other methods evaluated and was useful in its ability to predict variability in DDI magnitude and pharmacokinetic parameters. Moreover, the MDM model allowed the automated prediction of the inhibition of parallel metabolic pathways and simulations of different dosing regimens.

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“…In the case of nifedipine, oral administration along with quinidine (184) or following a 1-h pretreatment period (185) did not result in a statistical increase in the calcium-channel antagonist's plasma levels, whereas more prolonged quinidine pretreatment was found to produce a significant change (186). Similarly, the time interval between the administration of itraconazole and triazolam determined the extent of the interaction (187). Thus, when only using a single dose of an inhibitor, an adequate period of time must be given to allow attainment of sufficiently high inhibitor levels in order for an interaction to be measurable.…”

Section: Dosing and Temporal Factorsmentioning

confidence: 99%

In Vitro and in Vivo Drug Interactions Involving Human Cyp3a

Thummel

Wilkinson

1998

Annu. Rev. Pharmacol. Toxicol.

762

515

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Cytochrome P4503A (CYP3A) is importantly involved in the metabolism of many chemically diverse drugs administered to humans. Moreover, its localization in high amounts both in the small intestinal epithelium and liver makes it a major contributor to presystemic elimination following oral drug administration. Drug interactions involving enzyme inhibition or induction are common following the coadministration of two or more CYP3A substrates. Studies using in vitro preparations are useful in identifying such potential interactions and possibly permitting extrapolation of in vitro findings to the likely in vivo situation. Even if accurate quantitative predictions cannot be made, several classes of drugs can be expected to result in a drug interaction based on clinical experience. In many instances, the extent of such drug interactions is sufficiently pronounced to contraindicate the therapeutic use of the involved drugs.

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The effect of ingestion time interval on the interaction between itraconazole and triazolam

Cited by 47 publications

References 15 publications

Accurate Prediction of Dose-Dependent CYP3A4 Inhibition by Itraconazole and Its Metabolites From In Vitro Inhibition Data

Accurate Prediction of Dose-Dependent CYP3A4 Inhibition by Itraconazole and Its Metabolites From In Vitro Inhibition Data

Comparison of different approaches to predict metabolic drug-drug interactions

In Vitro and in Vivo Drug Interactions Involving Human Cyp3a

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