title: Application of receiver operating characteristic analysis to refine the prediction of potential digoxin drug interactions.
abstract: In the 2012 Food and Drug Administration (FDA) draft guidance on drug-drug interactions (DDIs), a new molecular entity that inhibits P-glycoprotein (P-gp) may need a clinical DDI study with a P-gp substrate such as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 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.
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania, USA.
authors.forename: Harma
authors.initials: H
authors.lastname: Ellens
authors.forename: Shibing
authors.initials: S
authors.lastname: Deng
authors.forename: Joann
authors.initials: J
authors.lastname: Coleman
authors.forename: Joe
authors.initials: J
authors.lastname: Bentz
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Taub
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ragueneau-Majlessi
authors.forename: Sophie P
authors.initials: SP
authors.lastname: Chung
authors.forename: Krisztina
authors.initials: K
authors.lastname: Herédi-Szabó
authors.forename: Sibylle
authors.initials: S
authors.lastname: Neuhoff
authors.forename: Johan
authors.initials: J
authors.lastname: Palm
authors.forename: Praveen
authors.initials: P
authors.lastname: Balimane
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Masoud
authors.initials: M
authors.lastname: Jamei
authors.forename: Imad
authors.initials: I
authors.lastname: Hanna
authors.forename: Michael
authors.initials: M
authors.lastname: O'Connor
authors.forename: Dallas
authors.initials: D
authors.lastname: Bednarczyk
authors.forename: Malin
authors.initials: M
authors.lastname: Forsgard
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chu
authors.forename: Christoph
authors.initials: C
authors.lastname: Funk
authors.forename: Ailan
authors.initials: A
authors.lastname: Guo
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Hillgren
authors.forename: Libin
authors.initials: L
authors.lastname: Li
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Pak
authors.forename: Elke S
authors.initials: ES
authors.lastname: Perloff
authors.forename: Ganesh
authors.initials: G
authors.lastname: Rajaraman
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.forename: Jan-Shiang
authors.initials: JS
authors.lastname: Taur
authors.forename: Dietmar
authors.initials: D
authors.lastname: Weitz
authors.forename: Heleen M
authors.initials: HM
authors.lastname: Wortelboer
authors.forename: Cindy Q
authors.initials: CQ
authors.lastname: Xia
authors.forename: Guangqing
authors.initials: G
authors.lastname: Xiao
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Yamagata
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Lee
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D003663:Decision Trees; D004077:Digoxin / Q000493:pharmacokinetics*; D004347:Drug Interactions; D006801:Humans; D012372:ROC Curve; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004077:Digoxin