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Spirapril

A Preliminary Review of its Pharmacology and Therapeutic Efficacy in the Treatment of Hypertension

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Abstract

Synopsis

Spirapril is a non-sulfhydryl angiotensin converting enzyme (ACE) inhibitor pro-drug which is converted to the active metabolite spiraprilat following oral administration, and which has been evaluated primarily for the treatment of hypertension. In dose-finding studies of patients with mild to severe hypertension, spirapril ≥6mg once daily produced reductions in blood pressure of approximately 10 to 18mm Hg (systolic) and 7 to 13mm Hg (diastolic) [24-hour postdose trough readings at the end of the treatment period]. Blood pressure normalisation (trough diastolic blood pressure ≤90mm Hg) had occurred in 29 to 50% of patients at the end of these investigations. The dose-response curve for spirapril appears to be flat for doses of 6 to 24mg once daily. Comparisons with other ACE inhibitors are limited in number, and further studies are required before the relative antihypertensive efficacy of spirapril can be fully evaluated. However, in single, well controlled clinical trials, spirapril produced similar reductions in blood pressure to those seen with enalapril or captopril. When given as monotherapy or in combination with hydrochlorothiazide, spirapril may off er potential advantages over the calcium antagonist nitrendipine. Spirapril is generally well tolerated and produces an adverse event profile similar to that of other ACE inhibitors.

Data from small studies suggest that spirapril can be used without dosage adjustment in patients with renal impairment, as a consequence of its dual renal and hepatic clearance mechanisms. This is in contrast to most ACE inhibitors, which are eliminated by a predominantly renal mechanism that results in accumulation of the active metabolite when renal function is impaired. However, the utility of spirapril in this patient group has yet to be fully determined because of conflicting data regarding its effects on renal function.

Thus, spirapril is an effective antihypertensive agent which is well tolerated. Further comparative trials are needed to fully determine its efficacy with respect to other ACE inhibitors, and a better understanding of its effects on renal function will clarify its role in hypertensive patients with renal failure.

Pharmacodynamic Properties

Spirapril is a prodrug which, when metabolised to its active diacid form spiraprilat, has potent activity against angiotensin converting enzyme (ACE). Inhibition of plasma ACE activity by spirapril has been demonstrated in numerous animal models, through direct measurement of ACE activity or by attenuation of angiotensin I-induced pressor responses. In patients with hypertension, oral spirapril produced short term (measured at 1 or 4 hours) inhibition of plasma ACE activity of between 75 and ≥90%, while longer term assessment (up to 6 months) yielded reductions in ACE activity of between 33 and 86%.

Significant reductions in blood pressure have been achieved with spirapril in numerous clinical trials involving patients with hypertension (see Therapeutic Efficacy section). In addition, spirapril produced reductions in vascular resistance in patients with hypertension or congestive heart failure. Reductions of ≈8 to 17% in a number of structural parameters associated with left ventricular (LV) hypertrophy (posterior wall thickness, LV mass and interventricular septal wall thickness) have been reported for spirapril in humans, confirming favourable findings from animal models of this condition. Limited results suggest that spirapril exerts much of its positive effect on LV hypertrophy by significantly reducing thickening of the LV posterior wall.

In volunteers or patients with normal renal function, spirapril appears to have no significant adverse effects on glomerular filtration rate or renal blood flow. However, the effects of spirapril in patients with renal impairment have yet to be fully characterised, since existing data for this indication are limited and contradictory.

Pharmacokinetic Properties

Following oral administration, the mean bioavailability of spirapril is 50%. Conversion of spirapril to its active diacid metabolite occurs rapidly, with maximum plasma concentrations (Cmax) of spiraprilat reached 1.8 to 3.0 hours after an oral spirapril dose. The disposition of spiraprilat in plasma is biphasic, with an initial phase half-life of 1.5 to 2.2 hours. High affinity binding of spiraprilat to ACE is responsible for a typical terminal elimination half-life of ~t30 to 40 hours. Elimination of spiraprilat occurs by both renal and nonrenal (hepatic) mechanisms. Spiraprilat does not exhibit any clinically significant accumulation (as measured by trough plasma concentrations 24 hours postdose) in patients with renal failure and dosage adjustment is not required. The pharmacokinetics of spiraprilat are altered in the elderly [30% increase in area under the concentration-time curve (AUC) and Cmax] and in patients with liver disease (30% decrease in AUC).

Therapeutic Efficacy

In several dose-finding studies, spirapril doses of between 6 and 24mg once daily had similar efficacy in reducing blood pressure in patients with mild to severe hypertension. Blood pressure normalisation (24-hour postdose trough reading <90mm Hg at the end of the treatment period) was observed in 29 to 50% of patients in these trials, while approximate mean reductions in trough systolic and diastolic blood pressure at study endpoints were 10 to 18mm Hg and 7 to 13mm Hg, respectively. Spirapril doses of <6mg once daily were generally less effective than higher doses, producing blood pressure normalisation in about 12% of patients and mean reductions in systolic and diastolic blood pressure of approximately 4 to 9mm Hg and 3 to 7mm Hg, respectively. When compared with blood pressure normalisation in 15 and 22% of patients with placebo, spirapril 6 to 24mg once daily yielded normalisation in 35 to 50% of patients.

Results from several clinical studies comparing spirapril with other antihypertensive agents are available, although direct comparisons with other ACE inhibitors are limited in number. Spirapril produced reductions in blood pressure similar to those seen with enalapril (18/17 vs 19/14mm Hg; n = 201) or captopril (10/10 vs 9/9mm Hg; n = 169) in well-controlled studies. Spirapril 12 to 24mg once daily produced a significantly higher rate of blood pressure normalisation (37%) than the calcium antagonist nitrendipine 20 to 40mg once daily (24%) in 213 patients with moderate to severe hypertension who were treated for 8 weeks.

Spirapril 3 to 6mg once daily was effective in reducing hypertension in elderly patients and appeared to have similar efficacy to isradipine in a single comparative study in this indication. Isolated reports of similar antihypertensive efficacy to that seen with isradipine in patients with diabetic nephropathy, and superior efficacy over atenolol, hydrochlorothiazide and isradipine in patients with sleep apnoea require confirmation.

Tolerability

Spirapril has a tolerability profile which is broadly similar to that of other ACE inhibitors, the most common adverse events reported in dose-finding and comparative trials being dizziness (up to 10.7%), headache (up to 13.1%) and fatigue (1.8 to 6.0%) [pooled n = 736]. The rates of these events, and of others commonly reported with ACE inhibitors, were generally similar for spirapril and placebo. The incidence of cough with spirapril (0 to ~t4%) in the few studies which provided this information appeared to be lower than values reported for other members of this drug class (typical range 1 to 10%, with peak incidences of between 15 and 25%), although direct prospective comparisons with other ACE inhibitors are required to confirm this finding. First-dose hypotension has not been reported in studies of spirapril. In the few direct clinical comparisons published to date, rates for adverse events or patient withdrawals with spirapril were similar to those with captopril and lower than those with enalapril or nitrendipine.

Dosage and Administration

Clinical trial data suggest that an oral spirapril dosage of 6mg once daily is as effective as higher dosages in reducing blood pressure in patients with hypertension. In elderly patients, spirapril 3 to 6mg once daily has demonstrated significant antihypertensive efficacy. Results from patients with renal impairment [creatinine clearance (CLCR) <80 ml/min] indicate that dosage adjustment is not necessary in this context, in contrast to most other ACE inhibitors. However, spirapril should not be used in patients with severe renal failure (CLCR <30 ml/min), given the absence of definitive information regarding its effects on renal function.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Stuart Noble & Eugene M. Sorkin

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Various sections of the manuscript reviewed by: J.E. Carlsen, Medicon A/S, Copenhagen, Denmark; P.E. de Leeuw, Department of Internal Medicine, University Hospital, Maastricht, The Netherlands; G.J. Fairhurst, Hypertension Research Unit, St. Helens, England; D.B. Frewin, Faculty of Medicine, University of Adelaide, Adelaide, South Australia, Australia; W.H. Frishman, Department of Medicine, Montefiore Medical Center, New York, New York, USA; C.E. Halstenson, Drug Evaluation Unit, Hennepin County Medical Center, Minneapolis, Minnesota, USA; P.A. Meredith, Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland; T. Ogihara, Department of Geriatric Medicine, Osaka University Medical School, Osaka, Japan; H. Okunishi, Department of Pharmacology, Shimane Medical University, Izumo, Japan; G. Olivetti, Department of Pathology, University of Parma, Parma, Italy; P.A. Phillips, Department of Medicine, Austin and Repatriation Hospital, Heidelberg, Victoria, Australia; G.P. Reams, Department of Medicine, University of Missouri-Columbia, Columbia, Misssouri, USA; B. Tomlinson, Department of Clinical Pharmacology, Prince of Wales Hospital, Shatin, Hong Kong; M.A. Weber, Hypertension Center, Veterans Administration Medical Center, Long Beach, California, USA; W.B. White, Section of Hypertension and Vascular Diseases, University of Connecticut Health Center, Farmington, Connecticut, USA.

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Noble, S., Sorkin, E.M. Spirapril. Drugs 49, 750–766 (1995). https://doi.org/10.2165/00003495-199549050-00008

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