EFFECT OF HYDROCHLOROTHIAZIDE ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF THE ANGIOTENSIN-II BLOCKER IRBESARTAN

The primary objective of this study was to assess the effect of hydroc hlorothiazide on the pharmacokinetics of irbesartan in patients with m ild-to-moderate hypertension. In addition, this study compared the pha rmacodynamic and tolerability profiles of irbesartan administered both alone and in combination with hydrochlorothiazide. The study consiste d of a placebo lead-in period (period A) to establish the stability of blood pressure (seated diastolic blood pressure 95 to 110 mm Hg), a 7 -day, single-blind treatment period (irbesartan 150 mg every day) (per iod B), and a 7-day, double-blind treatment period [irbesartan 150 mg every day plus either placebo (n = 18) or hydrochlorothiazide 25 mg ev ery day (n = 18)] (period C). Non-Black men and women 45 to 65 years o f age with hypertension were included. The pharmacokinetic profile [ma ximum concentration of irbesartan in plasma (C-max), time taken to rea ch C-max (t(max)), and the area under the plasma concentration versus time curve during a dosage interval (AUC(tau))] of irbesartan was unaf fected by the addition of hydrochlorothiazide. Mean chan in 24-hour AU C values for seated blood pressures from day 7 of period B to 7 of per iod C were significantly lower in patients treated with irbesartan plu s hydrochlorothiazide compared with those of patients treated with irb esartan plus placebo. Plasma angiotensin II levels, plasma renin activ ity, and urinary excretion of sodium, chloride and potassium were sign ificantly increased, whereas urinary aldosterone and creatinine excret ion remained unchanged with concomitant hydrochlorothiazide administra tion. Adding hydrochlorothiazide to irbesartan: (a) does not alter the pharmacokinetics of irbesartan, (b) produces further reductions in bl ood pressure, (c) produces further increases in plasma angiotensin II levels and plasma renin activity, and (d) is not associated with any c linically important tolerability concerns.