Comparing Various In Vitro Prediction Criteria to Assess the Potential of a New Molecular Entity to Inhibit Organic Anion Transporting Polypeptide 1B1.

摘要: Evaluation of organic anion transporting polypeptide (OATP) 1B1-mediated drug-drug interactions (DDIs) is an integral part drug development and recommended by regulatory agencies. In this study we compared various prediction methods cutoff criteria based on in vitro inhibition data to assess the potential a new molecular entity inhibit OATP1B1 vivo. (eg, IC50 , fu,p ) vivo dose, Cmax change area under curve [AUC]) for 11 substrates 61 inhibitors were obtained from literature Drugs@FDA, which include 107 clinical (in vivo) DDI studies. Substrate dependency variability values noted. addition ratio unbound or total systemic concentration (Imax,u Imax maximum inhibitor at inlet liver (Iu,in,max was used estimation "R value" where R = 1 + Iu,in,max /IC50 . Based our analyses, /Ki ≥ 0.1, 1.04, 1.1 seem be appropriate reducing false-negative (FN) predictions. However, as with 1.1, 0.1 1.04 resulted higher false positives (FPs) lower true negatives (TNs). Imax,u 0.02, 1.25 alone, combined criterion 1.25, reasonable determine need perform studies similar positive negative predictive values. Possible reasons FP FN different decision should considered when interpreting results, determination needs understood minimized.