Fosinopril

Summary

Synopsis

Fosinopril is a phosphinic acid prodrug which, after oral administration, undergoes rapid hydrolysis to its active diacid, the angiotensin converting enzyme (ACE) inhibitor fosinoprilat. Unlike other ACE inhibitors, fosinoprilat has a compensatory dual route of elimination and is cleared by the liver and kidneys. Thus, in patients with diminished renal function increased hepatic clearance of fosinoprilat is noted and, similarly, in patients with diminished hepatic function increased renal clearance seems to occur. Because of this compensatory elimination, fosinopril therapy for all patients can begin with the same recommended dosage.

Fosinopril 10 to 40mg administered once daily is an effective antihypertensive regimen that has shown efficacy similar to that of enalapril 5 to 10 mg/day, propranolol 80 to 160 mg/day, hydrochlorothiazide 25 to 50 mg/day and sustained release nifedipine 40 mg/day in preliminary clinical trials.

Generally, fosinopril is well tolerated and adverse events associated with the drug are usually mild and similar to those associated with other ACE inhibitors. Thus, fosinopril appears to be a useful alternative to certain ‘established’ agents used for treating patients with essential hypertension.

Pharmacodynamic Properties

In ex vivo studies, fosinopril has ACE inhibitory potency approximately 3 times that of captopril, similar to that of enalapril, half that of lisinopril and a quarter that of ramipril. Fosinopril more effectively inhibits ACE in brain and heart than in kidney, lung and aorta. In normotensive subjects, single oral doses of fosinopril 10 to 640mg completely inhibit plasma ACE activity within 1 hour of administration.

Single (10 to 640mg) and multiple (5 to 40 mg/day) oral doses of fosinopril administered to normotensive volunteers and hypertensive patients significantly increase plasma renin activity (57 to 400%) but have a variable effect on plasma aldosterone levels.

In hypertensive patients, single and multiple oral doses of fosinopril (10 to 40 mg/day) significantly reduced resting mean arterial (10 to 14%), systolic (10 to 14%) and diastolic (6 to 17%) blood pressure, and systemic vascular resistance (14 to 27%). Cardiac output (+6 to +10%), stroke volume (+6 to +11%) and peak ejection (+18%) and peak filling (-h 16%) rates were all increased after multiple dose regimens. Additionally, significant reductions in end-systolic wall stress, left ventricular septal wall thickness and left ventricular mass, and a significant increase in velocity of circumferential fibre shortening occurred after fosinopril administration to patients with hypertension.

A 4-to 12-week fosinopril regimen did not significantly alter mean cerebral blood flow and the regional distribution of cerebral blood flow, despite marked reductions in blood pressure in hypertensive patients.

Fosinopril 10 to 40 mg/day significantly reduced renovascular resistance (14%) without significantly altering renal blood flow, glomerular filtration rate and filtration fraction in 10 hypertensive patients.

Pharmacokinetic Properties

After oral administration, fosinopril is slowly and incompletely absorbed, but is then rapidly converted to its active diacid, fosinoprilat, by esterases in the gastrointestinal mucosa and liver. Approximately 34% of a single oral fosinopril 10mg dose is absorbed after administration to healthy volunteers, and peak plasma fosinoprilat concentration (C_max), time to C_max, area under the plasma fosinoprilat concentration-time curve and fosinoprilat bioavailability values have ranged from 99 to 140 μg/L, 2.8 to 3.1 hours, 1035 to 1132 μg/L · h, and 25 to 29%, respectively. Fosinopril has a linear pharmacokinetic profile across the dose range 10 to 640mg and, during multiple-dose fosinopril administration, no significant accumulation occurs.

Fosinoprilat has a low steady-state volume of distribution (9.8 to 10.6L) after intravenous administration to healthy volunteers and is cleared slowly from the body (total body clearance 1.55 to 2.35 L/h). Elimination is both renal and hepatic; less than 1% of an administered dose appears in the urine and faeces as unchanged fosinopril. The terminal elimination half-life of fosinoprilat has been estimated to range between 11.5 and 12 hours.

Fosinopril is unique among currently available ACE inhibitors since, in small numbers of patients with diminished renal or hepatic function, a compensatory increase in the alternative clearance mechanism occurs, thus maintaining total body clearance. In contrast to other ACE inhibitors, adjustment of fosinopril dosage therefore appears unnecessary in patients with diminished renal or hepatic function.

In healthy volunteers, age per se appears to have little influence on the pharmacokinetic profile of fosinoprilat.

Therapeutic Efficacy

In large-scale, dose-ranging studies in hypertensive patients, 8-to 12-week fosinopril regimens (5 to 80 mg/day) have significantly reduced systolic (8 to 16%) and diastolic (9 to 18%) blood pressure compared with baseline. Additionally, a dose-response relationship has been identified for fosinopril across the dosage range 5 to 80 mg/day, and response rates (usually the percentage of patients with sitting diastolic blood pressure ⩽ 90mm Hg and/or a reduction in this parameter of ⩾ 10% vs baseline) have ranged from 49 to 92%. Tolerance does not develop during long term fosinopril administration (12 months), and fosinopril has no clinically significant influence on heart rate.

A limited number of double-blind, comparative trials have shown that fosinopril possesses antihypertensive efficacy similar to that of enalapril, propranolol, hydrochlorothiazide and sustained release nifedipine. Fosinopril appears equally effective in elderly (⩾65 years) and younger hypertensive patients, as well as in Black and non-Black hypertensive patients.

Tolerability

Worldwide tolerability data are available for over 1500 fosinopril-treated individuals, of whom over 400 received the drug for 1 year or more. Fosinopril has been well tolerated in placebo-controlled studies; the incidence of adverse events (i.e. events related, possibly related or of unknown relationship to drug therapy) was not significantly different in 688 fosinopril recipients compared with 184 placebo recipients.

As with other ACE inhibitors, the most frequent adverse events which occur during fosinopril therapy are dizziness/lightheadedness (1.6 to 5.7% of patients), headache (3.2%), cough (2.2%), fatigue (1.5%) and gastrointestinal disorders [diarrhoea (1.5%), nausea/vomiting (1.2%)]. Unlike sulfhydryl-containing ACE inhibitors, fosinopril therapy is rarely associated with rash and taste disturbance (incidence 0.6 to 0.7%); sexual dysfunction occurred in 1.0% of fosinopril vs 1.1% of placebo recipients. Treatment withdrawal rates because of adverse events were 4.1% in fosinopril recipients and 1.1% in placebo recipients (no statistically significant difference between treatments).

Fosinopril is rarely associated with first-dose hypotension; the overall incidence of hypotensive symptoms (dizziness/lightheadedness, hypotension, orthostatic hypotension, syncope) was not significantly different in 144 elderly compared with 964 nonelderly hypertensive patients (7.0 vs 6.7%). Laboratory test abnormalities are also rare occurrences during fosinopril therapy; they necessitated treatment withdrawal in only 0.1 to 0.7% of patients and were not observed in patients treated with fosinopril for a year or more.

Dosage and Administration

In patients with hypertension, the recommended starting dosage of fosinopril is 10mg once daily. The dosage should be adjusted according to blood pressure response at peak and trough plasma fosinoprilat concentrations, and the usual fosinopril dosage required to maintain an adequate ‘trough response’ is 20 or 40mg once daily, although some patients show an additional response to 80mg once daily.

Fosinopril dosage adjustments do not appear necessary in patients with diminished renal or hepatic function, or in elderly hypertensive patients.