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
- 21 December 2009
- journal article
- research article
- Published by American Chemical Society (ACS) in Molecular Pharmaceutics
- Vol. 7 (2), 398-411
- https://doi.org/10.1021/mp900174z
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]/IC50 < 0.1 and [I2]/IC50 < 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 Cmax 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 [I2]. 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.Keywords
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