PHARMACOKINETICS AND PHARMACODYNAMIC EFFECTS OF THE ANGIOTENSIN-II ANTAGONIST VALSARTAN AT STEADY-STATE IN HEALTHY, NORMOTENSIVE SUBJECTS

Objective: Pharmacokinetics, pharmacodynamic effects and tolerability of 200 mg valsartan, once-daily for 8 days, were investigated in 16 he althy, normotensive volunteers on a normal sodium diet. Methods: This was a double-blind, placebo-controlled, randomized crossover study. Dr ug concentrations in plasma and urine, angiotensin II (Ang II) concent rations in plasma, systolic (SEP) and diastolic (DBP) blood pressure, heart rate (HR) in the supine position and 3 min after passive head-up tilting, as well as safety parameters (EGG, clinical chemistry and he matology, renal water and electrolyte excretion) were measured over 24 h after the first dose (day 1) and at steady state on day 8. Results: Absorption and distribution of valsartan were rapid (C-max, 2 h; t(1/ 2 lambda 1) < 1 h), followed by a slower terminal elimination phase (t (1/2 lambda 2), 6 h) on days 1 and 8, with little accumulation in plas ma (increase of 20% on day 8). Less than 10% of the dose was excreted unchanged in urine. The increase in plasma Ang II (C-max, 6 h) was sig nificantly enhanced at steady state. Supine SEP and DBP significantly decreased on day 8 only, by an average of -3.6 and -2.4 mmHg, respecti vely, versus placebo, without a concomitant increase in HR. Upon passi ve tilting, the increase in DBP, normally reinforced by sympathetic re nin release, was slightly but significantly blunted on day 1 (-2.0 mmH g) and day 8 (-4.0 mmHg) of treatment with valsartan Versus placebo. T he orthostatic reflex increase in HR was slightly enhanced compared wi th placebo by an average of 2.8 beats.min(-1) on day 1 and by 2.9 beat s.min(-1) on day 8. Valsartan was well tolerated and had no influence on EGG, clinical laboratory parameters, and water, electrolyte and uri c acid excretion. Conclusions: Pharmacokinetics of valsartan are uncha nged after multiple once-daily dosing, with little (expected) accumula tion in plasma. Effects of 200 mg valsartan on blood pressure in healt hy subjects on a normal sodium intake are small and become more promin ent after repeated dosing. Indirect evidence of AT(1) blockade by vals artan is demonstrated by an increase of plasma Ang II and by a blunted DBP response to passive tilting. The decrease in blood pressure at st eady state enhances the increase in plasma Ang II. Valsartan is well t olerated and is devoid of effects on water, electrolyte and uric acid excretion at 200 mg per day in healthy normotensive volunteers.