1. ¹Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research & Development, Sandwich, UK
2. ²Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Groton/New London, Connecticut, USA
3. ³Department of Clinical Pharmacology, Pfizer Global Research and Development, Groton/New London, Connecticut, USA
4. ⁴Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Ann Arbor, Michigan, USA
5. ⁵Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research & Development, La Jolla, California, USA
6. ⁶Current address: Genentech, Inc., 1-DNA Way MS-70, South San Francisco, California 94080, USA

Correspondence: CA Lee, (caroline.lee01@pfizer.com)

Received 17 April 2008; Accepted 28 August 2008; Published online 5 November 2008.

Abstract

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 (C_max)_,i,ss/C_max,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% C_max); 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 C_max).