Qualitative and quantitative assessment of drug-drug interaction potential in man, based on Ki, IC50 and inhibitor concentration.
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.
Blanchard
N
N
F Hoffmann - La Roche AG, Pharmaceuticals Division, CH-4070 Basel, Switzerland. nadege.blanchard@roche.com
Richert
L
L
Coassolo
P
P
Lavé
T
T
D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003627:Data Interpretation, Statistical; D004341:Drug Evaluation / Q000379:methods*; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010599:Pharmacokinetics; D011485:Protein Binding; D013379:Substrate Specificity
D001798:Blood Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D004364:Pharmaceutical Preparations