Abstract
In the 2012 Food and Drug Administration (FDA) draft guidance on drug-drug interactions (DDIs), a new molecular entity that inhibits P-glycoprotein (P-gp) may need a clinical DDI study with a P-gp substrate such as digoxin when the maximum concentration of inhibitor at steady state divided by IC₅&sub0; ([I&sub1;]/IC₅&sub0;) is ≥0.1 or concentration of inhibitor based on highest approved dose dissolved in 250 ml divide by IC₅&sub0; ([I&sub2;]/IC₅&sub0;) is ≥10. In this article, refined criteria are presented, determined by receiver operating characteristic analysis, using IC₅&sub0; values generated by 23 laboratories. P-gp probe substrates were digoxin for polarized cell-lines and N-methyl quinidine or vinblastine for P-gp overexpressed vesicles. Inhibition of probe substrate transport was evaluated using 15 known P-gp inhibitors. Importantly, the criteria derived in this article take into account variability in IC₅&sub0; values. Moreover, they are statistically derived based on the highest degree of accuracy in predicting true positive and true negative digoxin DDI results. The refined criteria of [I&sub1;]/IC₅&sub0; ≥ 0.03 and [I&sub2;]/IC₅&sub0; ≥ 45 and FDA criteria were applied to a test set of 101 in vitro-in vivo digoxin DDI pairs collated from the literature. The number of false negatives (none predicted but DDI observed) were similar, 10 and 12%, whereas the number of false positives (DDI predicted but not observed) substantially decreased from 51 to 40%, relative to the FDA criteria. On the basis of estimated overall variability in IC₅&sub0; values, a theoretical 95% confidence interval calculation was developed for single laboratory IC₅&sub0; values, translating into a range of [I&sub1;]/IC₅&sub0; and [I&sub2;]/IC₅&sub0; values. The extent by which this range falls above the criteria is a measure of risk associated with the decision, attributable to variability in IC₅&sub0; values.