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

Five patients with NYHA Class III CHF received 5 mg of fosinopril on each of 4 days. Hemodynamics were measured with a Swan-Ganz catheter after dosing on day 1. Measurements of plasma fosinoprilat, ACE activity, renin, and aldosterone were obtained. An E(max) model was used to fit the effect-site concentration and mean arterial pressure change, A linear model was used to fit the effect-site concentration and the pulmonary artery wedge pressure (PAWP) change. At steady state on day 4, AUC(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 plasma ACE inhibition, Plasma renin activity was unchanged, and mean plasma aldosterone level declined, E(max) modeling using fosinoprilat concentrations and mean arterial pressure showed good prediction of the pharmacodynamic effects from the effect-site concentration, A linear relationship was observed between the effect-site concentrations of fosinoprilat and PAWP. When expressed in an E(max) model, the pharmacodynamic actions of fosinopril in patients with CHF are a reflection of its pharmacokinetics.