Invasive Pharmacodynamics of Fosinopril in Patients with Congestive Heart Failure

Abstract

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 Emax 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, AUC0-24 was 1668 +/- 476 ng.hr/mL and Cmax was 143.5 +/- 33.6 ng/mL. The mean elimination half-life of fosinoprilat was 11.3 +/- 0.7 hours, and median Tmax occurred at 3 hours, corresponding to maximum plasma ACE inhibition. Plasma renin activity was unchanged, and mean plasma aldosterone level declined. Emax 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 Emax model, the pharmacodynamic actions of fosinopril in patients with CHF are a reflection of its pharmacokinetics.

Fosinopril: Emerging Considerations and Implications for Angiotensin‐Converting Enzyme Inhibitor Therapy

“…The absolute bioavailability of fosinopril in these studies was 29% in both controls and CHF patients (35).…”

“…There were no statistically significant differences between the CHF patients and controls with respect to C , , , or AUC. The absolute bioavailability of fosinopril in these studies was 29% in both controls and CHF patients (35).…”

Impact of Disease States on the Pharmacokinetics and Pharmacodynamics of Angiotensin‐Converting Enzyme Inhibitors

“…In cirrhotic patients, the deesterification of enalapril to enalaprilat was impaired compared to healthy counterparts, 72 although the impairment was not reported in another study 73 . Fosinopril showed a slower rate of conversion in hepatically impaired patients compared to healthy volunteers, although the extent of conversion to the active moiety was similar 75 …”

Does Chinese ethnicity affect the pharmacokinetics and pharmacodynamics of angiotensin-converting enzyme inhibitors?

“…(11.3 h) in Caucasian CHF patients from another single-dose study. 35 In CHF, where either the hepatic or renal elimination pathways may be affected, higher drug doses could produce adverse effects in the absence of dose proportionality. However, at steady state, over the oral fosinopril doses of 10, 20 and 40 mg/d there was dose proportionality in the Chinese CHF patients as indicated by both AUC and C max (Table 2).…”