01/04/2015 - Role of transporters in drug ADME

Application of receiver operating characteristic analysis to refine the prediction of potential digoxin drug interactions

Ellens H, Deng S, Coleman J, Bentz J, Taub ME, Ragueneau-Majlessi I, Chung S, Heredi-Szabo K, Neuhof S, Palm JE, Balimane P, Zhang L, Jamei M, Hanna IH, O’Connor M, Bednarczyk D, Forsgard M, Chu X, Funk C, Guo A, Hillgren KM, Li L, Pak A, Perloff E, Rajaraman G, Salphati L, Taur J, Weitz D, Wortelboer H, Xia C, Xiao G, Yamagata T, Lee CA. Drug Metab Dispos. 2013 Apr 25


In the 2012 Food and Drug Administration (FDA) draft guidance on drug-drug interactions (DDIs), a new molecular entity that inhibits P-glycoprotein (P-gp) may need a clinical DDI study with a P-gp substrate such as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 IC₅₀ ([I₁]/IC₅₀) is ≥0.1 or concentration of inhibitor based on highest approved dose dissolved in 250 ml divide by IC₅₀ ([I₂]/IC₅₀) is ≥10. In this article, refined criteria are presented, determined by receiver operating characteristic analysis, using IC₅₀ 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 IC₅₀ 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 [I₁]/IC₅₀ ≥ 0.03 and [I₂]/IC₅₀ ≥ 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 IC₅₀ values, a theoretical 95% confidence interval calculation was developed for single laboratory IC₅₀ values, translating into a range of [I₁]/IC₅₀ and [I₂]/IC₅₀ values. The extent by which this range falls above the criteria is a measure of risk associated with the decision, attributable to variability in IC₅₀ values.

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