Pharmacokinetic drug interaction studies with candesartan cilexetil

The aim of this series of studies was to determine the potential for pharmacokinetic interaction between candesartan (administered orally as the prodrug candesartan cilexetil) and hydrochlorothiazide (HCTZ), nifedipine, glibenclamide, warfarin, digoxin or the components of an oral contraceptive formulation. All studies were performed in healthy volunteers using randomised, crossover or add-on study designs. Candesartan cilexetil was administered orally at doses of 8, 12 or 16 mg. The pharmacokinetic parameters were determined for comparator agents and candesartan following administration of each agent alone or in combination. There were no changes in the drug plasma concentrations of nifedipine, glibenclamide, digoxin or oral contraceptives when co-administered with candesartan cilexetil. Co-administration of candesartan cilexetil caused a slight but significant decrease in the AUC of HCTZ. However, the 90% confidence intervals (CI) for AUC ratios for HCTZ when co-administered with candesartan cilexetil were within the defined limits of bioequivalence. Candesartan cilexetil produced a 7% decrease in trough plasma warfarin concentration but this had no effect on prothrombin time. Co-administration of candesartan cilexetil with HCTZ produced a statistically significant increase in the bioavailability and C-max values for candesartan (18% and 25%, respectively). However, this increase is not considered to be clinically relevant. No other co-administered drug (nifedipine, glibenclamide, digoxin, oral contraceptive) affected the pharmacokinetic parameters of candesartan. Candesartan cilexetil was well tolerated both alone and in combination with the other agents.