Viacoram Mechanism of Action

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, ACE inhibitors and calcium channel blockers. ATC code: C09BB04.
Pharmacology: Pharmacodynamics: Mechanism of action: Viacoram combines two antihypertensive compounds with complementary mechanisms to control blood pressure in patients with essential hypertension: amlodipine belongs to the calcium antagonist class and perindopril to the angiotensin converting enzyme inhibitors class of medicines.
The combination of these substances has an additive antihypertensive effect.
Pharmacodynamic effects: Perindopril: Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II (Angiotensin Converting Enzyme ACE). The converting enzyme, or kinase, is an exopeptidase that allows conversion of angiotensin I into the vasoconstrictor angiotensin II as well as causing the degradation of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE results in a reduction of angiotensin II in the plasma, which leads to increased plasma renin activity (by inhibition of the negative feedback of renin release) and reduced secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also results in an increased activity of circulating and local kallikrein-kinin systems (and thus also activation of the prostaglandin system). It is possible that this mechanism contributes to the blood pressure-lowering action of ACE inhibitors and is partially responsible for certain of their side effects (e.g. cough).
Perindopril acts through its active metabolite, perindoprilat. The other metabolites show no inhibition of ACE activity in vitro.
Amlodipine: Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.
The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces total ischaemic burden by the following two actions: Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina).
Clinical efficacy and safety: Perindopril/Amlodipine: In an 8-week, multicentre, randomised, double-blind, placebo-controlled, parallel group factorial study of 1581 patients with mild to moderate hypertension, perindopril 3.5 mg/amlodipine 2.5 mg clinically and statistically significantly reduced mean systolic/diastolic blood pressure (SBP/DBP) by 22.0/13.6 mmHg as compared to placebo (14.2/9.3 mmHg), perindopril 3.5 mg (16.3/9.7 mmHg) and amlodipine 2.5 mg (16.0/10.3 mmHg) (p<0.001 for all comparisons).
In a 6-month, multicentre, randomised, double-blind, active-controlled study, 1,774 patients with mild to moderate hypertension received either perindopril 3.5 mg/amlodipine 2.5 mg, uptitrated to 7 mg/5 mg, and 14 mg/10 mg, then to 14 mg/10 mg combined with indapamide 1.5 mg, or a valsartan-amlodipine strategy (valsartan 80 mg uptitrated to 160 mg and to valsartan/amlodipine 160 mg/5 mg, then to valsartan/amlodipine 160 mg/10 mg).
At 3 months, Viacoram strategy showed clinically and statistically significant mean decrease in SBP/DBP (25.9/16.9 mmHg) as compared to valsartan-amlodipine strategy (23.6/15.5 mmHg) (p<0.001 for all comparisons).
Blood pressure was controlled in 56.4% of patients treated with Viacoram strategy versus 49.0% with valsartan-amlodipine strategy (p=0.002), and the rate of responders was 87.4% versus 81.6%, respectively (p<0.001).
The superiority of Viacoram strategy over the valsartan-amlodipine strategy on blood pressure decrease and responder rates was observed from 1 month and maintained at each visit up to 6 months.
These results were confirmed in a 24-hour automated blood pressure monitoring (ABPM) performed in a subset of 1029 patients. At 3 months and 6 months, the decrease of the mean SBP and DBP over 24 hours was greater with Viacoram (15.5/9.4 mmHg and 17/10.4 mmHg, respectively) as compared to valsartan-amlodipine strategy (12.7/8.0 mmHg and 14.7/9.2 mmHg, respectively) (p≤0.001).
In the 8-month open-label follow-up on 1,554 patients, the safety profile of Viacoram was in line with the safety profiles of perindopril and amlodipine.
In a 9-month, multicentre, randomised, double-blind, active-controlled study, 3,270 patients with mild to severe hypertension received either perindopril/amlodipine 3.5 mg/2.5 mg, uptitrated to 7 mg/5 mg, 14 mg/5 mg then 14 mg/10 mg, or an irbesartan-hydrochlorothiazide strategy (irbesartan 150 mg, then irbesartan/hydrochlorothiazide 150 mg/12.5 mg, 300 mg/12.5 mg and 300 mg/25 mg).
The proportion of patients with controlled blood pressure statistically significantly increased with each of the perindopril/amlodipine treatment dose over each evaluation period (p<0.001 until 3 months, and p≤0.003 until 6 months).
After 6 months of treatment, the mean decrease in blood pressure was similar in the perindopril/amlodipine group (22.0/10.1 mmHg) and the irbesartan-hydrochlorothiazide group (22.5/9.6 mmHg) for both SBP (p=0.116) and DBP (p=0.050).
The most common adverse reactions in clinical trials were dizziness, cough and oedema (see Adverse Reactions).
The adverse reactions reported in clinical trials were in agreement with those anticipated from the safety profiles of the components perindopril and amlodipine.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) clinical trial data: Two large, randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of combination of an ACE-inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed.
Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
Pharmacokinetics: The rate and extent of absorption of perindopril and amlodipine from Viacoram are not significantly different, respectively, from the rate and extent of absorption of perindopril and amlodipine from individual tablet formulations.
Perindopril: Absorption: After oral administration, the absorption of perindopril is rapid and the peak concentration is achieved within 1 hour. The plasma half-life of perindopril is equal to 1 hour.
Perindopril is a prodrug. Twenty-seven percent of the administered perindopril dose reaches the bloodstream as the active metabolite perindoprilat. In addition to active perindoprilat, perindopril yields five metabolites, all inactive. The peak plasma concentration of perindoprilat is achieved within 3 to 4 hours.
As ingestion of food decreases conversion to perindoprilat, hence bioavailability, perindopril arginine should be administered orally in a single daily dose in the morning before a meal.
It has been demonstrated a linear relationship between the dose of perindopril and its plasma exposure.
Distribution: The volume of distribution is approximately 0.2 l/kg for unbound perindoprilat. Protein binding of perindoprilat to plasma proteins is 20%, principally to angiotensin converting enzyme, but is concentration-dependent.
Elimination: Perindoprilat is eliminated in the urine and the terminal half-life of the unbound fraction is approximately 17 hours, resulting in steady-state within 4 days.
Amlodipine: Absorption, distribution, plasma protein binding: After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
The bioavailability of amlodipine is not affected by food intake.
Biotransformation, elimination: The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.
Special populations: Paediatric population (age below 18 years): No pharmacokinetic data are available in the paediatric population.
Older people: The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. In elderly patients, amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients.
Initiation and increase of the dosage should take place with care in older people depending on renal function.
Elimination of perindoprilat is decreased in the elderly. Renal function should be monitored before increase of the dosage. Therefore, the usual medical follow-up will include monitoring of creatinine and potassium (see Dosage & Administration and Precautions).
Renal impairment: In patients with moderate renal impairment (Creatinine clearance between 30 ml/min to 60 ml/min), the initial recommended dose of Viacoram is 3.5 mg/2.5 mg every other day (see Dosage & Administration).
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Amlodipine is not dialyzable.
Elimination of perindoprilat is decreased in patients with heart or renal failure.
Therefore, the usual medical follow-up will include monitoring of creatinine and potassium (see Dosage & Administration and Precautions).
Hepatic impairment: Caution should be exercised in patients with liver disease (see Dosage & Administration and Precautions).
Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine resulting in a longer half-life and an increase in AUC of approximately 40-60%.
Dialysis clearance of perindoprilat is equal to 70 ml/min. Perindopril kinetics are modified in patients with cirrhosis: hepatic clearance of the parent molecule is reduced by half. However, the quantity of perindoprilat formed is not reduced and therefore no dosage adjustment is required (see Dosage & Administration and Precautions).
Toxicology: Preclinical safety data: Perindopril/Amlodipine: A preclinical safety study has demonstrated that the combination of perindopril and amlodipine was well tolerated in rats. The findings from the 13-week oral toxicity study in rats were consistent with those of perindopril and amlodipine when both active substances are administered alone. There were no new toxicities or increased severity of the toxicities which were associated with either component.
Perindopril: In the chronic oral toxicity studies (rats and monkeys), the target organ is the kidney, with reversible damage.
No mutagenicity has been observed in in vitro or in vivo studies.
Reproduction toxicology studies (rats, mice, rabbits and monkeys) showed no sign of embryotoxicity or teratogenicity. However, angiotensin converting enzyme inhibitors, as a class, have been shown to induce adverse effects on late foetal development, resulting in foetal death and congenital effects in rodents and rabbits: renal lesions and an increase in peri- and postnatal mortality have been observed.
No carcinogenicity has been observed in long term studies in rats and mice. Fertility was not impaired either in male or in female rats.
Amlodipine: Reproductive toxicology: Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.
Impairment of fertility: There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m² basis). In another rat study in which male rats were treated with amlodipine besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells.
Carcinogenesis, mutagenesis: Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on a mg/m² basis) was close to the maximum tolerated dose for mice but not for rats.
Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.
* Based on patient weight of 50 kg.