Evaluation of the pharmacokinetics of digoxin in healthy subjects receiving etoricoxib

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Digoxin is a well-recognized inotropic agent with a narrow therapeutic index. • Nonsteroidal anti-inflammatory drugs, including the selective cyclooxygenase-2 inhibitor etoricoxib, are very likely to be used in patients receiving digoxin due to the similar populations requiring the drugs. • Digoxin drug interactions should be assessed and described to clinicians when new drugs become available. WHAT THIS STUDY ADDS • This study is the first to provide the practitioner with a detailed description of the influence of etoricoxib on the pharmacokinetics of digoxin. • Due to the methods used, it shows that etoricoxib does not interfere with P-glycoprotein in the kidney, a method of digoxin disposition. • In addition, this paper provides confidence to the practitioner that there will be no clinically important reason to avoid the combination of the two drugs. AIMS Digoxin is a commonly prescribed cardiac glycoside with a narrow therapeutic index. The aim was to investigate whether the cyclooxygenase-2 selective nonsteroidal anti-inflammatory drug etoricoxib affects the steady-state pharmacokinetics of digoxin. METHODS This was a double-blind, randomized, placebo-controlled, two-period cross-over study. In each period, 14 healthy volunteers ranging in age from 21 to 35 years received oral digoxin 0.25 mg daily and were randomized to either etoricoxib 120 mg or matching placebo tablets once daily for 10 days. Trough digoxin plasma concentrations were analysed by linear regression to examine digoxin accumulation over time. RESULTS The geometric mean ratios (etoricoxib/placebo) for AUC0–24h, Cmax and urinary excretion were 1.06 (90% confidence interval 0.97, 1.17), 1.33 (1.21, 1.46) and 1.10 (1.00, 1.20), respectively. The median (range) for digoxin Tmax (h) values with etoricoxib and placebo were 0.5 (0.5, 1.5) and 1.0 (0.5, 1.5), respectively. Steady-state digoxin plasma concentrations were achieved by day 7 in each treatment period. No serious adverse experiences were reported. CONCLUSIONS Although etoricoxib 120 mg did produce an approximately 33% increase in digoxin Cmax, this increase does not appear to be clinically meaningful, as cardiotoxicity with digoxin has been associated with elevations in steady-state rather than peak concentrations. From these results, it appears that etoricoxib does not cause any changes in digoxin steady-state pharmacokinetics that would necessitate a dose adjustment.