Pharmacodynamics and Pharmacokinetics of Irbesartan in Patients With Mild to Moderate Hypertension

Abstract

Background: The pharmacodynamics (plasma angiotensin II [AII], plasma renin activity [PRA], renal function, blood pressure [BP], urinary excretion of major metabolites of pros tacyclin [PGI ₂-M], and thromboxane A₂ [TXA₂-M]) and pharmacokinetics of irbesartan were assessed in hypertensive patients.

Methods and Results: Twenty-four white patients with seated diastolic blood pressure 95 to 110 mmHg were randomized to double-blind irbesartan 300 mg or placebo once daily for 4 weeks, following a placebo lead-in. Irbesartan-treated patients had significantly greater 24- hour area under the curve values for mean change from baseline in AII and PRA versus pla cebo-treated patients on day B15 (AII [pg.h/mL]: 261 ± 515 vs 12 ± 51; PRA [(ng/mL/h).h]: 74 ± 162 vs -2 ± 14; P values < .05). Irbesartan significantly lowered BP without clinically important changes in renal function. Irbesartan had no effect on 24-hour urinary TXA₂-M excretion, but significantly increased 24-hour PGI₂-M excretion versus placebo on day B29 (20.7 ± 23 pg/mg creatinine vs -2.3 ± 43 pg/mg creatinine; P < .05). Pharmacokinetics were comparable to those from previous studies. The hourly relationship between plasma irbesartan concentration and antihypertensive effect indicated a broad, clockwise hysteresis, with peak concentration occurring at 1.5 hours, whereas peak antihypertensive effect occurred at 4 hours.

Conclusions: Irbesartan increases plasma AII and PRA and lowers BP consistent with AT₁ receptor blockade, without clinically important effects on renal function.