The effect of telmisartan on the steady-state pharmacokinetics of digoxin in healthy male volunteers

A multiple-dose, open-label, two-period, crossover randomized study was con ducted in 12 healthy male volunteers to investigate the effect of multiple- dose telmisartan on the steady-state pharmacokinetics of digoxin. On day 1 of a 7-day medication period, subjects received a loading dose of digoxin 0 .5 mg in the morning, followed by an evening dose of digoxin 0.25 mg, eithe r alone or together with telmisartan 120 mg administered in the morning. On the subsequent 6 days, either digoxin 0.25 mg or digoxin 0.25 mg together with telmisartan 120 mg was administered once daily in the morning. Each 7- day medication period was separated by a washout period of greater than or equal to 14 days. A steady-state plasma concentration-time profile was asse ssed for digoxin during each period and for telmisartan during the period w ith the combined treatment. Multiple-dose telmisartan administered with dig oxin resulted in higher serum digoxin concentrations than those observed af ter digoxin given alone. Geometric mean AUC(144-168), C-max and C-min value s for digoxin when given in combination with telmisartan were higher by 22% , 50%, and 13%, respectively, compared with values when given alone. Howeve r, the 90% confidence interval for the geometric mean of C-min was within t he predefined 80% to 125% range of no interaction. During combination medic ation, digoxin t(max) was shorter and C-max/AUC(144-168) increased, suggest ing that the rise in digoxin C-max may be due to more rapid drug absorption . Study medications were well tolerated with the incidence, nature, and int ensity of adverse events being similar during both medication periods. Also , no changes in vital signs or clinical laboratory tests were observed duri ng the study. Although there was some evidence for a pharmacokinetic intera ction between digoxin and telmisartan found in this study the safety and to lerability of digoxin were unaffected by concurrent administration of telmi sartan in the study population. Since any symptoms of overdose are related only to steady state and nor peak concentrations and due to the fact that t here was a lack of effect on serum trough levels of digoxin in this study i t is unlikely that the findings have any clinical relevance. The magnitude of increase in digoxin concentrations is comparable with increases observed with administration of calcium antagonists, carvedilol, ACE inhibitors suc h as captopril, and antiarrhythmic drugs such as amiodarone, quinidine, and propafenone. Monitoring of serum digoxin concentrations should be consider ed when patients first receive telmisartan and in the event of any changes in telmisartan dose. (C) 2000 the American College of Clinical Pharmacology.