Pharmacokinetic-pharmacodynamic interactions of candesartan cilexetil and losartan

Background The variability of the blood pressure response to blockade of th e angiotensin II type 1 receptor is influenced by renin status and pharmaco kinetics and pharmacokinetic-pharmacodynamic interactions. Objective To compare the pharmacokinetic-pharmacodynamic interactions of tw o doses of an ester prodrug of a noncompetitive angiotensin II type 1 recep tor antagonist, candesartan cilexetil, at 8 and 16 mg, with those of the re ference angiotensin II type 1 receptor blocker, losartan, at the standard d ose (50 mg), in a human model that controls renin status. Design and methods In a double-blind placebo-controlled crossover study, we compared the effects on renin and mean blood pressure over 24 h of single oral doses of candesartan cilexetil at 8 and 16 mg and losartan at 50 mg in 16 sodium-depleted normotensive subjects. Results The area under the curve (0-24 h) for plasma active renin did not d iffer significantly between 8 mg candesartan cilexetil and 50 mg losartan, but was significantly higher for 16 than for 8 mg candesartan cilexetil or for 50 mg losartan. The area under the curve (0-24 h) for the fall in mean blood pressure with 16 mg candesartan cilexetil (-197 +/- 96 mmHg/h) was si gnificantly greater than that for placebo (-112 +/- 81 mmHg/h; P < 0.05) bu t the difference was not statistically significant compared with either 8 m g candesartan cilexetil (-158 +/- 95 mmHg/h) or 50 mg losartan (-144 +/- 66 mmHg/h). The area under the curve (0-24 h) for the fall in mean blood pres sure did not significantly differ between 8 mg candesartan cilexetil, 50 mg losartan and placebo. The area under the curve (0-24 h) for plasma active renin was significantly correlated to that for plasma levels of the active metabolite of losartan, EXP 3174 (r = 0.65, n = 16, P < 0.01). No such corr elation was detected for each single dose of candesartan cilexetil but a do se-response relationship was present when both doses were combined. Conclusions The pharmacodynamic effects of a single oral dose of 16 mg cand esartan cilexetil are greater than those of 50 mg losartan and 8 mg candesa rtan cilexetil. The variability in the pharmacokinetic-pharmacodynamic inte raction is less pronounced for candesartan than for EXP 3174, which could r esult in reduced variability of the blood pressure effects in patients. J H ypertens 1999, 17:561-568 (C) Lippincott Williams & Wilkins.