Drug–Drug Interactions Mediated Through P‐Glycoprotein: Clinical Relevance and In Vitro–In Vivo Correlation Using Digoxin as a Probe Drug

The clinical pharmacokinetics and in vitro inhibition of digoxin were examined to predict the P‐glycoprotein (P‐gp) component of drug–drug interactions. Coadministered drugs (co‐meds) in clinical trials (N = 123) resulted in a small, ≤100% increase in digoxin pharmacokinetics. Digoxin is likely to show the highest perturbation, via inhibition of P‐gp, because of the absence of metabolic clearance. In vitro inhibitory potency data (concentration of inhibitor to inhibit 50% P‐gp activity; IC50) were generated using Caco‐2 cells for 19 P‐gp inhibitors. Maximum steady‐state inhibitor systemic concentration [I], [I]/IC50 ratios, hypothetical gut concentration ([I2], dose/250 ml), and [I2]/IC50 ratios were calculated to simulate systemic and gut‐based interactions and were compared with peak plasma concentration (Cmax),i,ss/Cmax, ss and area under the curve (AUC)i/AUC ratios from the clinical trials. [I]/IC50 < 0.1 shows high false‐negative rates (24% AUC, 41% Cmax); however, to a limited extent, [I2]/IC50 < 10 is predictive of negative digoxin interaction for AUC, and [I]/IC50 > 0.1 is predictive of clinical digoxin interactions (AUC and Cmax).