INVASIVE PHARMACODYNAMICS OF FOSINOPRIL IN PATIENTS WITH CONGESTIVE-HEART-FAILURE

Five patients with NYHA Class III CHF received 5 mg of fosinopril on e ach of 4 days. Hemodynamics were measured with a Swan-Ganz catheter af ter dosing on day 1. Measurements of plasma fosinoprilat, ACE activity , renin, and aldosterone were obtained. An E(max) model was used to fi t the effect-site concentration and mean arterial pressure change, A l inear model was used to fit the effect-site concentration and the pulm onary artery wedge pressure (PAWP) change. At steady state on day 4, A UC(0-24) was 1668 +/- 476 ng.hr/mL and C-max was 143.5 +/- 33.6 ng/mL. The mean elimination half-life of fosinoprilat was 11.3 +/- 0.7 hours , and median T-max occurred at 3 hours, corresponding to maximum plasm a ACE inhibition, Plasma renin activity was unchanged, and mean plasma aldosterone level declined, E(max) modeling using fosinoprilat concen trations and mean arterial pressure showed good prediction of the phar macodynamic effects from the effect-site concentration, A linear relat ionship was observed between the effect-site concentrations of fosinop rilat and PAWP. When expressed in an E(max) model, the pharmacodynamic actions of fosinopril in patients with CHF are a reflection of its ph armacokinetics.