Perindopril Arginine: Benefits of a New Salt of the ACE Inhibitor Perindopril

Written By: Sam Savage

Published Date: June 10, 2007 Last Edited: June 10, 2007

By Telejko, Elwira

Key words: Acceptability – L-Arginine – Bioequivalence – Perindopril – Shelf life – Stability ABSTRACT

Background: The efficacy of the angiotensin-converting enzyme (ACE) inhibitor perindopril in the treatment of hypertension, stable coronary artery disease, and heart failure is well established. The reduced stability of the current salt, perindopril-tert-butylamine, in extreme climatic conditions has prompted research into more stable compounds. This article presents stability and bioequivalence results for a new L-arginine salt of perindopril.

Methods: Drug stability studies were performed on nonsalified perindopril, perindopril-tert-butylamine, and perindopril arginine in closed and open containers. The bioequivalence of perindopril arginine was tested in 36 healthy male volunteers in an open-label, randomized, two-period, crossover pharmacokinetic study. A consumer study was carried out in 120 patients to assess preference for a simplified packaging using a high-density polyethylene canister designed for distribution to all climatic zones.

Results and discussion: Perindopril arginine is 50% more stable than perindopril-tert-butylamine, which increases the shelf life from 2 to 3 years. At the revised dosage (perindopril arginine 5-10 mg/day corresponds to perindopril-tert-butylamine 4-8 mg/day), the new salt is equivalent in terms of pharmacokinetics, efficacy, safety, and acceptability. The consumer studies indicate a preference for the new packaging, with 62% of patients nominating the canister as better than the blister packs.

Conclusion: The new perindopril arginine salt is equivalent to perindopril-tert-butylamine and more stable, and can be distributed to climatic zones III and IV without the need for specific packaging. The patient preference for the new packaging could have positive implications for compliance.

Introduction

The angiotensin-converting enzyme (ACE) inhibitor perindopril is one of the most effective drug treatments for cardiovascular disease1-5. Perindopril is indicated in essential hypertension, in stable coronary artery disease to reduce the risk of cardiac events in patients with a history of myocardial infarction (MI) and/or revascularization, and in the treatment of symptomatic heart failure. Because of this extensive range of indications for perindopril at all stages of the cardiovascular disease continuum and its efficacy and acceptability, this agent has become extremely popular in many countries. The currently available salt of perindopril is a salt of ferf-butylamine. It has a shelf life of about 2 years in countries with a temperate climate, and requires special packaging in countries with high temperatures and relative humidity (RH). This has led Servier, the research-based company that discovered and developed perindopril, to sponsor research to further improve the product by increasing its shelf life and stability. This is important because of the varying – and often difficult – conditions of transport, storage, and delivery in different parts of the world, with large variations in temperature and RH. The article describes investigations into the bioequivalence and stability of the new L-arginine salt of perindopril.

ACE inhibition with perindopril

ACE inhibitors act via blockade of the conversion of angiotensin I to angiotensin II, thereby reducing the complex and widespread effects of the latter. Since ACE also inactivates the breakdown of bradykinin, ACE inhibitors effectively increase bradykinin, which promotes the formation of vasodilators, including the formation of nitric oxide (NO). Improvement in the angiotensin II-bradykinin balance has a number of beneficial actions on the cardiovascular system, including antihypertensive and antiatherosclerotic effects6- 8.

Perindopril is a prodrug that is metabolized in the liver to its active diacid metabolite perindoprilat. Perindopril is rapidly and extensively absorbed9, and perindoprilat has one of the highest tissue ACE affinities among the ACE inhibitors10. Tissue ACE affinity is related to its lipophilicity, which determines the extent of its penetration into endothelial and adventitial tissue and atherosclerotic plaque. Specific inhibition of tissue ACE increases the antiatherosclerotic action of an ACE inhibitor, as well as its effects on left ventricular hypertrophy and remodeling3.

The onset of activity of perindopril is longer than the other members of the class, and maximal inhibition of ACE occurs 8 h after a single oral dose of perindopriliert-butylamine 8mg. The inhibition is still 70% effective 24 h after intake10. The clinical consequence of this is that perindopril has the highest trough to peak ratio of all the ACE inhibitors11, between 75% and 100%. At a once-daily dosage, this translates into effective 24-h blood pressure control.

The clinical efficacy of perindopril is well established in hypertension12,13, heart failure14, and diabetic nephropathy15. Moreover, the cardiovascular effects of ACE inhibition with perindopril go well beyond this, as shown by four recent trials2-5. First, the Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS) showed that 4 years of a perindopril-based regimen caused a significant 28% decrease in the risk of recurrent stroke and a 26% reduction in the risk of major vascular events1. second, the EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA)2 demonstrated that 4 years’ treatment with perindopril on top of other standard preventive therapies produced a 20% reduction in the relative risk of cardiovascular death, nonfatal MI, and resuscitated cardiac arrest. These effects have been linked to the action of the ACE inhibitor in correcting endothelial dysfunction2,10,16. Third, the Perindopril and Remodeling in Elderly with Acute Myocardial Infarction (PREAMI) study showed that treatment of patients with preserved left ventricular function with perindopril for 1 year produced a significant 22% reduction in the absolute risk of death, hospitalization for heart failure, or cardiac remodeling3. Finally, the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA), the largest European study ever performed in hypertension, including 20000 patients4, demonstrated a significant advantage of the amlodipine/perindopril combination over a more traditional atenolol/bendroflumethiazide combination. The results of ASCOT-BPLA are already having an impact on clinical practice17.

Perindopril has a good acceptability profile. As expected for an ACE inhibitor, the most commonly reported adverse event is dry cough, which is generally mild and disappears upon cessation of treatment. The rates of adverse events for perindopril compare favorably with other members of the ACE inhibitor class, with low rates of cough, hypotension, and withdrawals, as demonstrated in long-term clinical trials10,18.

Drug stability and climatic zones

Perindopril thus has a major role to play in one of the most important classes in the cardiovascular field. Any change in salt should therefore be considered carefully, with appropriate investigations of stability, bioequivalence, and therapeutic efficacy. Before we describe these studies for perindopril, we should review the factors affecting drug stability and bioavailability.

The stability of a therapeutic agent is defined as its resistance to unfavorable chemical, physical, biological, and microbiological processes occurring during production and storage. The shelf life of a drug is the period of time during which its pharmacological activity does not decrease below a certain value. A drug is deemed suitable for use if no more than about 5% of the active substance has undergone degradation and the degradation products are not toxic19. The chemical stability of a therapeutic agent can be assessed by investigating the chemical processes occurring during storage. Climatic factors, such as humidity, oxygen, light, and temperature, also have a major influence on drug stability.

Assessment of the stability of a drug is one of the necessary requirements for marketing authorization by the drug regulatory agencies. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) was set up to unify the quality, safety, and efficacy requirements for therapeutic agents entering the pharmaceutical market. The ICH provides recommendations that are accepted by the major regulatory agencies. ICH guidelines20 for studies on quality of pharmaceutical raw materials (ICH Q3A) and ready-to-use therapeutic preparations (ICH Q3B) include the obligation to monitor the impurities arising during the manufacturing process and identify any degradation products that may be produced during storage. The toxicity of these compounds should also be determined.

Separate ICH guidelines on stability20’21 set out reference values for temperature and RH for each of four defined climatic zones: climatic zone I, temperate, 24[degrees]C/35% RH, for long-term studies; and climatic zone IV, hot and humid, >24[degrees]C/75% RH. These climatic zones are summarized in Table 1, together with examples of countries assigned to each zone for the purposes of drug stauivalent to climatic zone IV are used for accelerated aging studies. Even if the pure pharmacologically active substance is stable under given conditions, it may undergo degradation when stored under extreme conditions of increased temperature and RH (climatic zones III and IV)22″26. This degradation may involve the interaction of the pharmacologically active substance with excipients, decreasing the content of active substance and modifying parameters such as the rate of release of active substance and its solubility27. Moreover, degradation products may also cause adverse events, for example, the degradation of tetracycline under storage conditions of high temperature and RH not only changes the physical and chemical parameters of the drug (color change from light yellow to dark brown), but also increases its nephrotoxicity28’29.

The use of a prodrug like perindopril increases the bioavailability of an agent because the prodrug has a better lipophilicity than the active metabolite (perindoprilat), while the degradation of a prodrug during storage may significantly reduce the bioavailability of the active metabolite in vivo, and decrease therapeutic efficacy. When a new salt is sought, the aim is to improve the balance between bioavailability and drug stability.

Table 1. Definitions of climatic zones and examples of countries2′. RH, relative humidity

Stability of perindopril arginine

When perindopril was first marketed in 1988, the terf-butylamine salt of perindopril was selected for distribution because impurities could be easily isolated during the crystallization phase. The stability of this salt in conditions corresponding to climatic zones III and IV meant that different packaging was necessary for distribution to countries in those zones. In climatic zones I and II, perindopril-terf-butylamine is currently marketed in PVC/ aluminum blister packs, while a multicomponent type of packaging is used in climatic zones III and IV, involving PVC/aluminum blister packs overwrapped with a watertight bag containing a desiccant. Stability testing has proved this type of packaging to be efficient, but it is complicated and difficult to implement on a large scale.

Stability studies conducted according to the ICH guidelines have shown that perindopril may undergo degradation via two mechanisms: (i) at high RH, ester hydrolysis results in the formation of the poorly absorbed diacid; and (ii) at relatively high temperatures, cyclization and formation of lactam-type compounds lead to the degradation product known as Y31.

Studies on powdered perindopril indicate that the cyclization step can be almost entirely prevented by salification. When nonsalified perindopril and its tert-butylamine salt were stored in separate closed containers for 2 days at 100[degrees]C, the nonsalified perindopril completely degraded to Y31, whereas the perindopril-ferf-butylamine salt remained almost intact. However, when they were stored under the same conditions, but in open containers, the terf-butylamine salt also completely degraded to Y31 (Table 2). This can be explained by the volatility of feri- butylamine at high temperatures, leaving the unbound form of perindopril, which then undergoes degradation to Y31. Thus, salification with a volatile substance entails a potential risk for the stability of the product once the container has been opened.

A number of nonvolatile alternatives have been tested for the salification of perindopril. The arginine salt (Figure 1) was selected because it had the best balance between stability and hygroscopicity. The stability of the perindopril arginine salt was tested in closed and open containers for 2 days at 100[degrees]C, as described above. The arginine salt performed better in these tests than the tert-butylamine salt, and was 100% stable even in the open container (Table 2).

Substitution of the ferf-butylamine salt with perindopril arginine is also an attractive solution to the complex packaging of perindopril in climatic zones III and IV. The stability of the perindopril arginine formulation was tested for 6 months in a simple high-density polyethylene (HDPE) canister (Figure 2) with a desiccant under stressed conditions predictive of climatic zone IV (40[degrees]C/75% RH). The results show that the stability of the arginine salt in this simplified packaging is better than the stability of the tert-butylamine salt in the blister packs (Table 3). These changes will also have consequences for the shelf life of the product. Changing the salt to perindopril arginine increases the shelf life of perindopril by 50%, e.g., from 2 years to 3 years irrespective of the storage temperature.

Table 2. Comparative stability of nonsalified penndopnl, penndopnl argtnine, and perindopril-tert-butylamine stored in open or closed bottles at 100[degrees]C for 2 days

Figure 1. Molecular structure of the new angiotensin-converting enzyme (ACE) inhibitor perindopril as its L-arginine salt

Figure 2. Simplified packaging for perindopnl arginine in the form of a new high-density polyethylene (HDPE) canister

Table 3. Stability results obtained with penndopril arginine 5 mg packaged in canisters with desiccant compared with penndopnl-tert- butylamine 4 mg tablets packaged in aluminum/PVC blister packs, in terms of sum of degradation products (penndoprilat and Y31) remaining after 12 months at 25[degrees]C/60% relative humidity (RH) or 30[degrees]C/60% RH, or after 6 months at 40[degrees]C/75% RH

Bioequivalence of perindopril arginine and perindopril-tert- butylamine

A change in the salification of a compound necessarily leads to a change in quantity of substance per dosage unit, because of the change in molecular weight. The molecular weight of perindopril arginine (542.680) is nearly 25% greater than that of perindopril- terfbutylamine (441.615), and so the dosage changes accordingly. To achieve equimolar quantities and plasma concentrations of perindoprilat, a dosage of perindopril arginine 5 mg replaces perindopril-tert-butylamine 4 mg and a dosage of perindopril arginine 10mg replaces perindopril-tert-butylamine 8mg.

The pharmacokinetic properties of the two salts have been compared after single oral and intravenous administration to Wistar rats and repeated administration to beagle dogs for 7 days. Perindopril, perindoprilat, and their respective glucuronides were assayed using liquid chromatography with tandem mass spectrometry detection (LC-MS-MS). These preclinical experiments found perindopril arginine and perindopril-feri-butylamine to be comparable in terms of their absorption, distribution, metabolism, and elimination characteristics (Perindopril Arginine, Common Technical Document, Module 2). Their bioavailability was also found to be similar.

The bioequivalence of the two perindopril salts in humans has been examined in an open-label, randomized, two-period, crossover, pharmacokinetic study involving 36 healthy male volunteers (age 19- 52 years, mean 31.3+- 9.6 years; body mass index 20.1-27.4g/m^sup 2^, mean 23.3 +- 1.7kg/m^sup 2^). These subjects were randomly assigned to two groups. Each group received a single oral dose of immediate-release perindopril as either the arginine salt (10mg) or the tert-butylamine salt (2 x 4mg). After an 8-day washout period, each group received a single oral dose of the salt that they did not receive in the first test period. They were monitored for pharmacokinetic parameters (maximum plasma concentration (C^sub max^, time at maximum plasma concentration (t^sub max^), area under the plasma concentration-time curve (AUC^sub t^), and half-life (t^sub 1/2^), cardiovascular parameters (blood pressure (BP) and heart rate), and safety, before and for 12Oh after administration. A follow-up examination was performed 3-5 days after the last blood sample had been taken, including physical examination, electrocardiogram (ECG), BP, heart rate, and laboratory parameters (Perindopril Arginine, Common Technical Document, Module 3).

The bioequivalence of the two salts was demonstrated with perindopril arginine/perindopril-feri-butylamine AUC^sub t^ ratios of 96.3% (95% confidence interval (CI), 92-100%) for perindopril and 100% (95% CI, 92-108%) for perindoprilat (Table 4). The CIs are well within the recommended range of 80-125%. Similar ratios were found for the other pharmacokinetic parameters. The two salts had the same antihypertensive efficacy with no clinically significant changes in BP, laboratory parameters, vital signs, or ECG parameters.

Acceptability of perindopril arginine

The bioequivalence trial described above also recorded the acceptability profile of the perindopril arginine salt. There were two times fewer treatment-related adverse events with perindopril arginine (5.56%) than with perindopril-terf-butylamine (16.67%). The most common adverse event in this study was headache (Table 5).

Packaging of perindopril arginine

Consumer preference for the simplified HDPE canister described above (Figure 2) versus the blister pack has been evaluated in a sample of 120 patients. The sample included men and women aged 60- 70 years (50%) and consumers aged over 70 years (50%) accessed through three large pharmacies in Australia. All were receiving one or more chronic prescription medications. Of the sample nominated, 69% expressed an overall preference for the canister (perindopril arginine 5 and lOmg) compared with 31% (p

Table 4. Ratio of pharmacokinetic parameters for perindopril and penndoprilat (baseline corrected) following a single oral dose of perindopril arginine (Wmg) or perindopril-tert-butylamine (8mg) to 36 healthy male volunteers, including confidence intervals (CI). AUC^sub t^, area under the plasma concen 5. Emergent adverse events with perindopril arginine Wmg compared with perindopril-tert- butylamine 8mg: 2/36 (5.56%) participants had experienced two treatment-related emergent adverse events during the perindopril arginine treatment period; 6/36 (16.67%) participants had experienced nine treatment-related emergent adverse events during the perindopril-tert-butylamine treatment period. NOS, not otherwise specified; NAE, number of adverse events; n, number of patients reporting adverse event Discussion

The main features of the new and old salts of perindopril are compared in Table 6. The new perindopril arginine salt has been demonstrated to be safe and to have similar antihypertensive efficacy to the previous one, provided the dosage is revised due to the difference in molecular weight. The rates of treatment-related adverse events with the two perindopril salts indicate that the acceptability profile of the new perindopril arginine salt is at least as good as that of the perindopril-tert-butylamine one. The rates of emergent adverse events (Table 5) are in line with those observed in the large-scale trials with perindopril1’2. The low rate for cough is in agreement with previous reports of lower rates with perindopril than with other ACE inhibitors18.

The significance of drug stability studies has considerably increased due to the globalization of the pharmaceutical market, in which widely used medicinal products, such as perindopril, are manufactured in one or more countries, and then distributed worldwide and stored under extremely varied climatic conditions. The World Health Organization (WHO) has recognized the importance of this issue by recommending that stability studies should be carried out for drugs intended for ‘the global market/ using the conditions for climate zone IV30.

Figure 3. Preference for packaging: canister versus blister pack. Percentage of subjects (n=l 20) nominating the packaging they feel best suits each dimension

Table 6. Comparison of the main features of two perindopril salts, perindopnl arginine and perindopnl-tert-butylamine

In line with these recommendations, the increased stability and shelf life of the new perindopril arginine will permit the use of a simplified packaging in the form of a HDPE canister all over the world, even in climatic zone IV. This will considerably facilitate production and distribution. The patient approval of the packaging is one outcome of the change. This approval may be expected to have an influence on compliance, especially in these often-elderly patients. Compliance with perindopril treatment is already very good2 and could increase further with optimized packaging and improved acceptability.

Conclusion

The new salt of the ACE inhibitor perindopril as an arginine salt improves the stability of the product and increases its shelf life. Pharmacokinetic studies indicate that perindopril arginine can be expected to have at least equivalent antihypertensive efficacy to the previous one, with a revised dosage due to the difference in molecular weight of the two salts: perindopril arginine 5-10 mg replaces perindopril-terf-butylamine 4-8 mg. Therefore, the benefits demonstrated in large-scale trials performed with perindopril-tert- butylamine also apply to perindopril arginine. As a consequence, in the countries where it has been registered, perindopril arginine has been granted the same indications, i.e. hypertension, heart failure, and stable coronary artery disease. The improved stability of the new salt means that the same simplified packaging can be used in all climatic zones. Patients’ preference for the new canister can be expected to have further positive impact on compliance.

Acknowledgments

E. Telejko has received speaker fees and honoraria, as well as editorial assistance in the preparation of this article, from Servier.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-3839_6, Accepted for publication: 26 February 2007

Published Online: 29 March 2007

doi:10.1185/030079907X182158

Elwira Telejko

Studium Ksztalcenia Podyplomowego, Biatystok, Poland

Address for correspondence: Dr Elwira Telejko, Department of Postgraduate Education, Faculty of Pharmacy, Medical University of Bialystok, Kilinskiego Street 1, 15-222 Bialystok, Poland. Tel./ Fax: +48 85 748 55 02; [email protected]

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