title: Refining the in vitro and in vivo critical parameters for P-glycoprotein, [I]/IC50 and [I2]/IC50, that allow for the exclusion of drug candidates from clinical digoxin interaction studies.
abstract: The objective of this work was to further investigate the reasons for disconcordant clinical digoxin drug interactions (DDIs) particularly for false negative where in vitro data suggests no P-glycoprotein (P-gp) related DDI but a clinically relevant DDI is evident. Applying statistical analyses of binary classification and receiver operating characteristic (ROC), revised cutoff values for ratio of [I]/IC(50) < 0.1 and [I(2)]/IC(50) < 5 were identified to minimize the error rate, a reduction of false negative rate to 9% from 36% (based on individual ratios). The steady state total C(max) at highest dose of the inhibitor is defined as [I] and the ratio of the nominal maximal gastrointestinal concentration determined for highest dose per 250 mL volume defined [I(2)](.) We also investigated the reliability of the clinical data to see if recommendations can be made on values that would allow predictions of 25% change in digoxin exposure. The literature derived clinical digoxin interaction studies were statistically powered to detect relevant changes in exposure associated with digitalis toxicities. Our analysis identified that many co-meds administered with digoxin are cardiovascular (CV) agents. Moreover, our investigations also suggest that the presence of CV agents may alter cardiac output and/or kidney function that may act alone or are additional components to enhance digoxin exposure along with P-gp interaction. While we recommend digoxin as the probe substrate to define P-gp inhibitory potency for clinical assessment, we observed high concordance in P-gp inhibitory potency for calcein AM as a probe substrate.
authors.affiliation: Departments of Clinical Pharmacology, Pharmacokinetics, Groton/New London, Connecticut, Sandwich, UK.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Cook
authors.forename: Bo
authors.initials: B
authors.lastname: Feng
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Fenner
authors.forename: Sarah
authors.initials: S
authors.lastname: Kempshall
authors.forename: Ray
authors.initials: R
authors.lastname: Liu
authors.forename: Charles
authors.initials: C
authors.lastname: Rotter
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Smith
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Troutman
authors.forename: Mohammed
authors.initials: M
authors.lastname: Ullah
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Lee
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D002986:Clinical Trials as Topic; D004077:Digoxin / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D020128:Inhibitory Concentration 50; D004364:Pharmaceutical Preparations / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations; D004077:Digoxin