Pharmacokinetic-pharmacodynamic interactions of candesartan cilexetil and losartan

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Abstract
The variability of the blood pressure response to blockade of the angiotensin II type 1 receptor is influenced by renin status and pharmacokinetics and pharmacokinetic-Spharmacodynamic interactions. To compare the pharmacokinetic-pharmacodynamic interactions of two doses of an ester prodrug of a noncompetitive angiotensin II type 1 receptor antagonist, candesartan cilexetil, at 8 and 16 mg, with those of the reference angiotenisn II type 1 receptor blocker, losartan, at the standard dose (50 mg), in a human model that controls renin status. 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. The area under the curve (0–24 h) for plasma active renin did not differ 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 (−2197 ± 96 mmHg/h) was significantly greater than that for placebo (−112 ± 81 mmHg/h; P < 0.05) but the difference was not statistically significant compared with either 8 mg 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 pressure 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 correlation was detected for each single dose of candesartan cilexetil but a dose-response relationship was present when both doses were combined. The pharmacodynamic effects of a single oral dose of 16 mg candesartan cilexetil are greater than those of 50 mg losartan and 8 mg candesartan cilexetil. The variability in the pharmacokinetic-pharmacodynamic interaction is less pronounced for candesartan than for EXP 3174, which could result in reduced variability of the blood pressure effects in patients.