Qualitative and Quantitative Assessment of Drug-Drug Interaction Potential in Man, Based on Ki, IC50 and Inhibitor Concentration

Abstract

Strategies used to screen new drug entities as potential inhibitors of CYP450 enzymes are now widely used to select candidates in the drug discovery process. However, the information obtained based on IC50 values are usually more of qualitative nature. The aim of this study was to find out whether a more quantitative assessment of interaction potential could be achieved on the basis of the ratio I/Ki (I corresponds to inhibitor concentration). Ki values, in vivo data, namely plasma exposures under control condition vs in presence of inhibitors, were obtained from literature for 36 compounds. For a quantitative assessment, the following inhibitor concentrations were considered: I max and I in,max (respectively, maximum I in systemic circulation and in portal vein), I max,u and I in,max,u (respectively, maximum unbound I in systemic circulation and in portal vein). The predicted interaction was calculated as AUCinhibitor/AUCcontrol = 1 + I/Ki, where AUCcontrol and AUCinhibitor represent, respectively, the area under curve of the plasma concentration vs time profile under control conditions (ie without inhibitor) and with inhibitor. The use of I/Ki allowed a more quantitative estimation of the interaction potential. In this context, protein binding appeared to be a key parameter to be considered to avoid overestimation of DDI potential. Thus, 60% successful predictions could be achieved based on the ratio I max,u/Ki. Yet, some major deviations between in vivo DDI were obtained with this approach and the observations on the relevance of the inhibitor concentrations and the impact of binding need to be interpreted very cautiously in the absence of information on additional parameters such as fm and fh for example.

Necrosis of osteosarcoma cells induces the production and release of high‑mobility group box 1 protein

“…IC50 is typically used to measure the efficacy of a drug (28). In the present study, the IC50 values of DXR in the MG63 and U2OS cells were 496.9 and 424.6 ng/ml, respectively.…”

Inhibition of Human Liver Aldehyde Oxidase: Implications for Potential Drug-Drug Interactions

“…Previous attempts to define the value for [I] that best approximates the concentration of inhibitor at the enzyme site have used peripheral vein concentration, hepatic portal vein concentration, average plasma concentration, maximum plasma concentration, hepatic input concentration, and hepatocyte concentration (Blanchard et al, 2004;Ito et al, 2004;Bachmann, 2006). For each of these values, both bound and unbound fractions can be used.…”

Comparison of Different Algorithms for Predicting Clinical Drug-Drug Interactions, Based on the Use of CYP3A4 in Vitro Data: Predictions of Compounds as Precipitants of Interaction

“…Numerous researchers (Kanamitsu et al, 2000a;Blanchard et al, 2004;Ito et al, 2004;Brown et al, 2006;Galetin et al, 2008;Ohno et al, 2008) have used a variety of mathematical models that require static values of precipitant concentrations in the intestine and liver for the prediction of DDIs. However, at present, there is no consensus on the in vivo precipitant concentration that should be used.…”

“…However, in vivo it was shown to be an inducer of CYP3A4, and this effect was also seen in in vitro induction studies (Moore et al, 2000). Projecting potential clinical DDIs from in vitro data has progressed from specific endpoint analysis based on the relationship between the projected therapeutic concentration of the drug and its reversible binding affinity for the particular enzyme of interest (I/K i ) (Kanamitsu et al, 2000a;Tucker et al, 2001;Blanchard et al, 2004;Bachmann and Lewis, 2005) to a comprehensive analysis including the simultaneous evaluation of the potential impact of reversible inhibition, time-dependent inhibition, and induction (Fahmi et al, 2008b).…”