Single‐Dose and Steady‐State Pharmacokinetics of Fosinopril and Fosinoprilat in Patients with Hepatic Impairment

Abstract

The single-dose and steady-state pharmacokinetics of the angiotensin-converting enzyme (ACE) inhibitor fosinopril and its active diacid, fosinoprilat, were evaluated in 6 healthy volunteers and 12 patients with alcoholic cirrhosis. Fosinopril was administered at a dosage of 10 mg once daily for 14 days. Results in the two groups were similar, with no evidence of accumulation of fosinoprilat in hepatically impaired patients. Mean (+/- SD) maximum observed plasma concentrations of fosinoprilat in the healthy subjects were 112.0 +/- 67.2 ng/mL after the first dose and 144.1 +/- 61.7 ng/mL at steady-state. Corresponding values for the hepatically impaired patients were 111.4 +/- 40.1 ng/mL and 140.2 +/- 50.9 ng/mL. The area under the serum concentration versus time curve for healthy volunteers was 790.7 +/- 431.0 ng.hr/mL after the first dose and 940.3 +/- 400.4 ng.hr/mL at steady-state. Similar values were noted in hepatically impaired patients: 926.0 +/- 293.9 ng.hr/mL and 1,255.4 +/- 434.0 ng.hr/mL for first dose and steady-state, respectively. No statistically significant differences were detected in fosinoprilat pharmacokinetic values between healthy and hepatically impaired subjects. Absence of accumulation can be attributed to the dual route of elimination of fosinoprilat reported in previous studies. Renal excretion of fosinoprilat in hepatically impaired patients prevents increased accumulation. The present findings suggest that the starting dose of fosinopril used in hypertensive patients with normal renal and hepatic function can also be used in patients with hepatic impairment secondary to cirrhosis.

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

“…One study demonstrated no differences in mean blood pressure change, even though the AUC of enalaprilat was lower in the cirrhotic group than in the normal subjects, 72 whereas another showed no change in systolic blood pressure, but the decrease in diastolic blood pressure was comparable 73 . Ford et al showed no effect of fosinopril on blood pressure in either alcoholic cirrhotic patients or healthy volunteers, perhaps explained by these patients being normotensive at baseline 84 . Enalaprilat and lisinopril caused comparable decreases in blood pressure in normal subjects and cirrhotic patients; however, the mean baseline blood pressure was higher in the patients 76…”

Antihypertensive and Vasoprotective Effects of Fosinoprile in Patients With Arterial Hypertension

“…Для фозиноприла характерно меньшее количество побочных эффектов по сравнению с другими представителями этого класса лекарственных препаратов, в частности более редкое возникновение кашля, что позволяет рассчитывать на хорошую компла-ентность пациентов к лечению. Двойной компенсаторный путь выведения позволит назначать этот препарат пациен-там с нарушенной функцией почек [9][10][11].…”

The Place of Fosinopril in Evidence-Based Treatment of Patients With Arterial Hypertension

“…Отмечается край-не низкая частота возникновения сухого кашля [26]. Имеются доказательства, что сухой кашель, вызываемый другими иАПФ, ослабевает или даже полностью исчезает при переходе на прием фозиноприла [27,28]. Важен факт, что основные параметры фармакокинетики не раз-личаются у пожилых и молодых больных.…”