Perindopril erbumine (perindopril) is a prodrug ester of perindoprilat, an angiotensin converting enzyme (ACE) inhibitor. Perindopril 4 to 8mg once daily significantly reduces supine systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline values in hypertensive patients. These reductions are maintained for at least 24 hours, as evidenced by trough/peak ratios of >50%.
Vascular abnormalities associated with hypertension were improved or normalised during perindopril treatment. Perindopril 4 to 8mg once daily significantly decreased carotid-femoral aortic pulse wave velocity (PWV), improved arterial compliance, reduced left ventricular mass index and, in patients with recent cerebral ischaemia and/or stroke, preserved cerebral blood flow despite significantly reducing SBP and DBP. Further research is needed to establish the significance of promising results showing that reductions in aortic PWV were associated with reduced mortality in patients with end-stage renal failure, a third of whom received perindopril.
Response rates (numbers of patients with supine DBP ≤90mm Hg) were significantly higher with perindopril 4 to 8mg once daily (67 to 80%) than with captopril 25 to 50mg twice daily (44 to 57%) in 3 randomised double-blind trials. In other clinical trials, the antihypertensive effects of perindopril were similar to those of other ACE inhibitors (including enalapril) and calcium-channel antagonists. Combination treatment with perindopril and an antihypertensive agent from another treatment class provided additional benefits, either as first-line treatment or in patients failing to respond to monotherapy. Perindopril monotherapy was also effective in the elderly and in patients with hypertension and concomitant disease.
Perindopril has a similar adverse event profile to that of other ACE inhibitors; cough is the most common event reported during treatment, and is also the most common adverse event responsible for treatment withdrawal.
Conclusions: Perindopril is a well tolerated ACE inhibitor that is significantly better than captopril (in terms of response rates) in the treatment of hypertension, and as effective as other ACE inhibitors. Perindopril appears to reverse some of the vascular abnormalities associated with hypertension, including arterial stiffness and left ventricular hypertrophy, although further research is needed to confirm promising results regarding its ability to decrease associated cardiovascular morbidity and mortality. Results from ongoing studies will help confirm the place of perindopril in the treatment of hypertension; currently, it is an effective and well tolerated treatment for patients with mild to moderate essential hypertension.
Perindopril erbumine (perindopril) is a prodrug ester of perindoprilat, an angiotensin converting enzyme (ACE) inhibitor. Oral administration of perindopril dose-dependently decreases plasma ACE activity; the concentration of perindoprilat required to inhibit 50% of ACE activity (IC50) is 3.6 nmol/L at steady state. Maximal inhibition of ACE activity occurred 2 to 4 hours after perindopril 2,4 or 8mg at steady state, and inhibition of plasma ACE activity remained >70% 24 hours after single dose perindopril 4, 8 or 16mg. ACE inhibition was not affected by age or ethnicity, but was significantly increased compared with single dose values after multiple dose administration (15 days) in patients with severe renal failure.
In patients with hypertension, perindopril significantly reduces systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline levels, maintaining reductions for at least 24 hours (see Therapeutic Efficacy summary). Treatment with perindopril improved arterial and haemodynamic abnormalities associated with hypertension; carotid-femoral aortic pulse wave velocity (PWV) significantly decreased from baseline levels (−1.1 m/sec, p < 0.001) in a non-comparative 6-month study (n = 1703). Reductions in aortic PWV during anti-hypertensive treatment (71% of patients required medication, 46% of whom received perindopril 4 to 8mg every 48 hours alone or in combination with other antihypertensive agents) were associated with significant reductions in both cardiovascular and all-cause mortality in a cohort study involving 150 patients with end-stage renal failure. Treatment with perindopril, but not atenolol or nitrendipine, was positively correlated with survival.
Significant reductions in systemic vascular resistance and significant increases in arterial diameter, compliance and blood flow were seen during perindopril treatment in a number of studies. Intravenous perindoprilat 1mg restored the normal flow-dependent and cold-pressor test-induced dilatations in the coronary arteries of patients with hypertension. Perindopril did not significantly decrease cerebral blood flow in patients with hypertension and recent cerebral ischaemia or stroke (in 1 study, patients also had moderate to severe carotid stenosis or occlusion), although both SBP and DBP were significantly reduced.
Significant reductions from baseline values in left ventricular mass index (LVMI) were seen with perindopril 4 to 8 mg/day for 2 to 12 months in a number of clinical trials. LVMI decreased significantly from baseline by 13.55 g/m2 (p < 0.001) during treatment with perindopril 4 to 8mg once daily for 3 months in 741 patients with stable hypertension and moderate LV hypertrophy; smooth LV remodelling occurred, with the reduction in wall thickness matching the reduction in ventricular size. Other echocardiographic parameters were improved by perindopril in some studies, with significant decreases in diastolic wall and intraventricular septal thickness and increases in left ventricular relaxation.
Albuminuria in patients with hypertension and diabetes or nephropathy was significantly reduced during treatment with perindopril 2 to 8mg once daily. Perindopril did not adversely affect glycaemic control or lipid profiles.
After oral administration, perindopril undergoes extensive metabolic changes that include the formation of perindoprilat by hydrolysis. The bioavailability of perindopril ranges between 65.6 and 95.1%; 16.8% of an oral dose of perindopril is present in plasma as perindoprilat. Perindopril is 74% plasma protein-bound at steady-state concentrations and perindoprilat is 15% bound to plasma proteins.
Perindopril is rapidly absorbed, with a peak plasma concentration (Cmax) of 64.2 µg/L achieved 0.7 to 0.9 hours after single dose perindopril 4mg. Perindoprilat reached a Cmax of 4.7 µg/L at 3.6 hours post-dose. At therapeutic doses, both perindopril and perindoprilat display linear pharmacokinetics. The volume of distribution of perindopril in humans is low, at 0.22 L/kg; animal data suggest that perindopril distributes primarily to tissues with high ACE activity.
After absorption, perindopril either undergoes first-pass metabolism to form perindopril glucuronide (subsequently hydrolysed to perindoprilat glucuronide) or is hydrolysed to perindoprilat (primarily in the liver). Plasma concentrations of perindopril were negligible within 8 hours of drug administration; elimination half-life (t½β) values for perindopril, perindoprilat and perindoprilat glucuronide were 2.9, 10.9 and 1.7 hours, respectively. Both perindoprilat and perindoprilat glucuronide are renally cleared. In 1 study, within 96 hours of oral administration of radioactively labelled perindopril (dosage not stated), 75% of the dose was recovered in the urine and 25% in the faeces.
The pharmacokinetics of perindopril were not significantly different in patients with hypertension, compared with those in healthy volunteers. Significantly increased perindoprilat bioavailability was observed in the elderly. Perindoprilat Cmax, area under the plasma concentration-time curve and half life were significantly increased in patients with renal impairment, and reduced perindopril dosages are recommended in this patient group; in contrast, no clinically significant changes in pharmacokinetic parameters were seen in patients with hepatic impairment.
Perindopril significantly reduced SBP and DBP from baseline values in clinical trials involving patients with hypertension, with a dose-response effect for doses of ≤8mg. Rates of supine DBP ≤90mm Hg ranged from 67 to 80% in perindopril recipients, compared with 44 to 57% in captopril recipients (p ≤ 0.02), in 3 randomised double-blind 3-month trials. In other comparative trials, perindopril 4 to 8mg once daily produced similar mean reductions from baseline DBP and SBP to those seen with enalapril, ramipril, lisinopril and fosinopril.
Mean reductions from baseline supine SBP and DBP values did not differ significantly between perindopril recipients and those who received the calcium antagonists verapamil, diltiazem, isradipine and amlodipine in 4 randomised trials lasting for 2 to 6 months. Perindopril reduced supine DBP from baseline values significantly more than metoprolol in an 8-week trial in patients with left ventricular hypertrophy (by 13.2 vs 5.3%, respectively, p < 0.05). Response rates were significantly higher with perindopril than with atenolol in a 3-month double-blind study involving 171 patients (78 vs 58%, p < 0.05), although 1 small study (n = 25) found significantly greater reductions in supine SBP and DBP with atenolol.
Response rates and reductions from baseline supine SBP and DBP values did not significantly differ between patients who received perindopril and those who received combination therapy with amiloride/hydrochlorothiazide 5/50 to 10/100 mg/day in a 3-month randomised double-blind study (n = 165), although mean reductions in standing SBP were significantly greater with diuretic therapy (31.1 vs 24.6mm Hg with perindopril, p = 0.01). Mean reductions from baseline supine DBP values were significantly greater with perindopril than with combination therapy with amiloride and hydrochlorothiazide (7.9 vs 3.5%, p < 0.05) in another study, although dosages for amiloride/hydrochlorothiazide (2.5/25 and 5/50 mg/day) were lower.
Combining perindopril with hydrochlorothiazide 25 mg/day or indapamide 1.25 mg/day resulted in higher response rates and greater reductions in BP than those observed with any agent alone. Patients who failed to respond to perindopril monotherapy experienced significant reductions in supine SBP and DBP with the addition of hydrochlorothiazide 12.5 to 50 mg/day, nifedipine sustained release 10mg twice daily or indapamide 1.25 mg/day.
In large noncomparative trials, mean SBP/DBP fell by 28/18mm Hg in 43 245 patients who completed 1 year of treatment with perindopril 2 to 8 mg/day alone or in combination with other antihypertensive agents, and normalisation of BP (supine DBP ≤90mm Hg) was achieved in 95.7% of 23 460 outpatients who received perindopril-based treatment for 6 months. Most patients (≥80%) were receiving perindopril monotherapy.
Trough/peak ratios for supine DBP were >70% for perindopril 2, 4, 8 or 16mg once daily in a dose-finding study involving 293 patients with hypertension. Although data are limited, trough/peak ratios for perindopril appeared to be as good as or better than those for other antihypertensive agents and are >50% for doses ≥4mg, as recommended by the US Food and Drug Administration for once daily administration of antihypertensives.
In patients aged ≥70 years (n = 2927), perindopril 2 to 8 mg/day (alone or in combination with other antihypertensive agents) significantly reduced mean supine SBP and DBP in a 6-month noncomparative study, with 94.2% of patients achieving a mean DBP ≤90mm Hg. Response rates (DBP <90mm Hg) were 59% in a similar 1-year study involving 2256 patients aged ≥80 years.
Perindopril was also effective in the treatment of patients with hypertension and a range of concomitant diseases, including type 2 diabetes mellitus, ischaemic heart disease and nephropathy with proteinuria. Parameters of concomitant disease were either improved or were not adversely affected during treatment with perindopril.
Perindopril is well tolerated, with a similar adverse effect profile to that of other ACE inhibitors. The most common adverse events reported during treatment with perindopril 2 to 8mg once daily for 1 year were cough, GI upset/dyspepsia and asthenia in a postmarketing surveillance study involving 47 351 patients with hypertension; 16.3% of patients spontaneously reported an adverse event. 8.5% of patients withdrew from treatment; the majority (59%) did so because of suspected adverse reactions (most often cough). Perindopril 4 to 8 mg/day was at least as well tolerated as captopril 50 to 100 mg/day, diltiazem 60 to 180mg twice daily, amlodipine 5 to 10 mg/day or combination therapy with amiloride 5 to 10 mg/day and hydrochlorothiazide 50 to 100 mg/day in clinical trials.
Dosage and Administration
The recommended starting dosage of perindopril in patients with hypertension is 2mg once daily, increased as necessary to a maximum recommended daily dosage of 8mg according to European guidelines (dosage guidelines may differ in other countries). As perindoprilat is renally excreted, dosage reductions are necessary in patients with renal impairment. No dosage adjustments are necessary in the elderly or in patients with hepatic impairment.
Perindopril is contraindicated in pregnancy and in patients with a history of angioneurotic oedema in association with ACE inhibitor therapy. Potassium supplements and potassium-sparing diuretics should not be used in combination with perindopril.
KeywordsAngiotensin Converting Enzyme Pulse Wave Velocity Angiotensin Convert Enzyme Inhibitor Perindopril Left Ventricular Mass Index
- 2.Alderman M, Arakawa K, Beilin L, et al. 1999 World Health Organization — International Society of Hypertension Guidelines for the Management of Hypertension. Blood Press 1999; 8 Suppl. 1: 9–43Google Scholar
- 20.Agabiti Rosei E, Corea L, Leonetti G, et al. A double-blind assessment, perindopril vs verapamil, of the effects on office and 24 HR ambulatory blood pressure and on left ventricular morphology [abstract no. 708]. European Society of Hypertension; 7th European Meeting on Hypertension; 1995 Jun 9–12, Milan, ItalyGoogle Scholar
- 23.Galiavitch A, Shlyakhto E, Konradi A, et al. Effects of antihypertensive treatment on heart structure in mild essential hypertension [abstract]. J Hypertens 1998 Jun; 16 Suppl. 2: S242Google Scholar
- 29.Gisclon LG, Moyer M. Pharmacokinetics (PK) and pharmacodynamics (PD) of perindopril (P) and its active metabolite, perindoprilat (PL) in healthy subjects [abstract]. Clin Pharmacol Ther 1992 Feb; 51: 153Google Scholar
- 33.Plouin P-F, Alhenc-Gélas F, Aldigier J-C, et al. Effect of perindopril (S-9490) on blood pressure and renin-angiotensin aldosterone system in hypertensive men [poster abstract]. Clin Exp Hypertens A 1987; A9(11): 1988Google Scholar
- 41.Savi L, Mettimano M, Montebelli MR, et al. Effects of perindopril on left ventricular mass and on diastolic function in mild-to-moderate hypertension. J Drug Dev Clin Pract 1995 Jun; 7: 85–90Google Scholar
- 45.Asmar RG, Topouchian JA, Benetos A, et al. Non-invasive evaluation of arterial abnormalities in hypertensive patients. J Hypertens 1997; 15 Suppl. 2: S99–107Google Scholar
- 51.Meyer C, Nielsen FS, Sato A, et al. Beneficial effect of acute ACE inhibition on vasomotion and myocardial perfusion in type II diabetics with left ventricular hypertrophy [abstract no. 914]. Circulation 1997 Oct 21; 96(8) Suppl.: 1–166Google Scholar
- 56.Sihm I, Schroeder AP, Aalkjaer C, et al. Regression of media-to-lumen ratio of human subcutaneous arteries and left ventricular hypertrophy during treatment with an angiotensinconverting enzyme inhibitor-based regimen in hypertensive patients. Am J Cardiol 1995 Nov 24; 76: 38E–40EPubMedCrossRefGoogle Scholar
- 57.Bonner G, Lederle RM, Scholze J, et al. Therapeutic safety of perindopril in the treatment of mild hypertension with concomitant nephropathy. Arzneim Forsch Drug Res 1993; 43(8): 852–5Google Scholar
- 58.Stumpe KO, Overlack A. A new trial of the efficacy, tolerability, and safety of angiotensin-converting enzyme inhibition in mild systemic hypertension with concomitant diseases and therapies. Perindopril Therapeutic Safety Study Group (PUTS). Am J Cardiol 1993 Jun 24; 71: 32E–7EGoogle Scholar
- 60.Tykarski A, Kopatka P, Posadzy-Malaczynska A, et al. Comparison of the effects of angiotensin II antagonists and ACE inhibitors on renal handling of uric acid in hypertensive patients [abstract]. Nephrol Dial Transplant 1999 Sep; 14: A62Google Scholar
- 76.Funck-Brentano C, Lecocq B, Jaillon P, et al. Effects of food on the pharmacokinetics and ACE-inhibition of perindopril in healthy volunteers. In: Velasco M, Israel A, Romero E, et al., editors. Recent advances in pharmacology and therapeutics. Amsterdam: Elsevier Science Publishers BV, 1989: 277–80Google Scholar
- 79.2001 Mosby’s GenRx [online]. 2001 Mosby’s Gen Rx. Available from http://www.mosbysgenrx.com/t-doc.htm [Accessed 2000 Nov 13]
- 82.Myers MG. A dose-response study of perindopril in hypertension: effects on blood pressure 6 and 24 h after dosing. Perindopril Multicentre Dose-Response Study Group. Can J Cardioll 1996 Nov; 12: 1191–6Google Scholar
- 83.Zannad F, Bernaud CM, Fay R. Double-blind, randomized, multicentre comparison of the effects of amlodipine and perindopril on 24 h therapeutic coverage and beyond in patients with mild to moderate hypertension. General Physicians Investigators’ Group. J Hypertens 1999 Jan; 17: 137–46PubMedCrossRefGoogle Scholar
- 85.Safar M, Salzman V, Brault Y, et al. Safety and efficacy of perindopril/indapamide fixed combination in mild-to-moderate hypertension [abstract]. J Hypertens 1996 Jun; 14 Suppl. 1: S225Google Scholar
- 88.Nedogoda SV, Petrov VI. The differences between ACE inhibitors trough to peak ratios at 24-hour ambulatory monitoring (cross-over study) [abstract]. J Hypertens 1998 Jun; 16 Suppl. 2: S247Google Scholar
- 90.Yoshinaga K, Saruta T, Abe K, et al. Clinical evaluation of monotherapy with perindopril, an ACE inhibitor, in the treatment of essential hypertension: double-blind parallel comparison with enalapril. Rinsholyaku 1997; 13: 4259–97Google Scholar
- 92.Honos G, Gossard D, Auger P, et al. Once daily perindopril versus slow release diltiazem in the treatment of mild to moderate essential hypertension. Canadian Study Group on Perindopril. Can J Cardiol 1994 Nov; 10 Suppl. D: 8D–12DGoogle Scholar
- 95.Black HR, Saunders E. Efficacy and safety of perindopril and hydrochlorothiazide in stage I–III hypertension. Perindopril PE Study Group. J Vasc Med Biol 1994; 5(5-6): 191–8Google Scholar
- 96.Letellier P, Overlack A, Agnes E, et al. Perindopril plus nifedipine versus perindopril plus hydrochlorothiazide in mild to severe hypertension: a double-blind multicentre study. Multicentre Study Group on Treatment Association with Perindopril. J Hum Hypertens 1994 Feb; 8: 145–9PubMedGoogle Scholar
- 101.Fressinaud P, Berrut G, Gallois H. Antihypertensive activity and acceptability based on clinical and laboratory parameters of perindopril: chief results in 23,460 mild to moderate hypertension patients treated for 6 months in general practice [in French]. Ann Cardiol Angeiol Paris 1993 Jan; 42: 51–9PubMedGoogle Scholar
- 108.Denolle T, Rennuci J-F, Poggi L, et al. Efficacy and tolerance of a angiotensin converting enzyme, perindopril, in 2256 hypertensive patients aged 80 years or over treated for one year [abstract]. Am J Hypertens 1994 Apr; 7 (Pt 2): 50AGoogle Scholar
- 110.Nalbantgil S, Gürün C, Yilmaz H, et al. The effect of antihypertensive treatment with Perindopril and Lacidipine on the incidence of silent ischemia in patients with hypertension [abstract]. Cardiovasc Drugs Ther 1999 Mar; 13: 56Google Scholar
- 111.PROGRESS: Perindopril Protection Against Recurrent Stroke Study. ESH 1999, Milan, Italy (Data on file)Google Scholar
- 112.ABPI compendium of data sheets and summaries of product characteristics. 1999–2000 edition, 1999–2000Google Scholar
- 123.Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999 Feb 20; 353: 611–6PubMedCrossRefGoogle Scholar
- 125.Henderson JR, Gomma AH, Fox KM. European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease. In: Fox K, Remme WJ, editors. ACE inhibition and ischaemic heart disease. London: Science Press, Ltd, 1999:51–8Google Scholar