Database analyses for the prediction of in vivo drug–drug interactions from in vitro data

Abstract

AimsIn theory, the magnitude of an in vivo drug-drug interaction arising from the inhibition of metabolic clearance can be predicted using the ratio of inhibitor concentration ([I]) to inhibition constant ( K i ). The aim of this study was to construct a database for the prediction of drug-drug interactions from in vitro data and to evaluate the use of the various estimates for the inhibitor concentrations in the term [I]/ K i . MethodsOne hundred and ninety-three in vivo drug-drug interaction studies involving inhibition of CYP3A4, CYP2D6 or CYP2C9 were collated from the literature together with in vitro K i values and pharmacokinetic parameters for inhibitors, to allow calculation of average/maximum systemic plasma concentration during the dosing interval and maximum hepatic input plasma concentration (both total and unbound concentration). The observed increase in AUC (decreased clearance) was plotted against the estimated [I]/ K i ratio for qualitative zoning of the predictions. ResultsThe incidence of false negative predictions (AUC ratio > 2, [I]/ K i < 1) was largest using the average unbound plasma concentration and smallest using the hepatic input total plasma concentration of inhibitor for each of the CYP enzymes. Excluding mechanism-based inhibition, the use of total hepatic input concentration resulted in essentially no false negative predictions, though several false positive predictions (AUC ratio < 2, [I]/ K i > 1) were found. The incidence of true positive predictions (AUC ratio > 2, [I]/ K i > 1) was also highest using the total hepatic input concentration. ConclusionsThe use of the total hepatic input concentration of inhibitor together with in vitro K i values was the most successful method for the categorization of putative CYP inhibitors and for identifying negative drug-drug interactions. However this approach should be considered as an initial discriminating screen, as it is empirical and requires subsequent mechanistic studies to provide a comprehensive evaluation of a positive result.

Integrated in Vitro Analysis for the in Vivo Prediction of Cytochrome P450-Mediated Drug-Drug Interactions

“…2A). This contrasts somewhat with a previous report , which estimated correctly the in vivo magnitude of the quinidine interaction with desipramine, metoprolol, and imipramine using an external database (Ito et al, 2004). Interrogation of the two datasets indicates that a minor (ϳ2-fold) difference in both fu b and K i values results in the ϳ4-fold difference in ␦AUC prediction.…”

Cyclosporine A, but Not Tacrolimus, Shows Relevant Inhibition of Organic Anion-Transporting Protein 1B1-Mediated Transport of Atorvastatin

“…The unbound concentration of an inhibitor is usually applied in this respect. However, it has been suggested that, at least for metabolic interactions, it may be more appropriate to use the total concentration in these calculations (Ito et al, 2004;Bachmann and Lewis, 2005). In this study, estimates based on total CsA concentrations show that the degree of OATP1B1 PS int inhibition would be more than 94% throughout the dosing interval, with a maximum of 99% (Fig.…”

Drug Interactions of Thalidomide with Midazolam and Cyclosporine A: Heterotropic Cooperativity of Human Cytochrome P450 3A5

“…In addition, previous findings have shown spontaneous nonenzymatic hydrolysis (Schumacher et al, 1965). To address the inhibitory potential of a drug, it was considered important to determine an inhibition constant (K i ) (Ito et al, 2004). However, there is little information about inhibition by thalidomide thus far.…”