Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: ACE inhibitors and calcium channel blockers: enalapril and lercanidipine.

ATC code: C09BB02

Vasodip Combo is the fixed combination of an ACE inhibitor (enalapril) and a calcium channel blocker (lercanidipine), two antihypertensive compounds with complementary mechanism of action to control blood pressure in patients with essential hypertension.

Enalapril

Enalapril maleate is the maleate salt of enalapril, a derivative of two amino acids, L-alanine and L- proline. Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase which 
catalyses the conversion of angiotensin I to the vasopressor agent angiotensin II. After absorption, enalapril is hydrolysed to enalaprilat, which inhibits ACE. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to the removal of negative feedback of renin release) and decreased aldosterone secretion.

Since ACE is identical to kininase II, enalapril may also inhibit the degradation of bradykinin, a potent vasodepressor peptide. However, the role of this mechanism in the therapeutic effects of enalapril is still not understood.

Although the mechanism by which enalapril reduces blood pressure is primarily attributed to suppression of the renin-angiotensin-aldosterone system, enalapril is antihypertensive even in patients with low renin levels.

Administration of enalapril to hypertensive patients reduces both supine and standing blood pressure, without a significant increase in heart rate.

Symptomatic postural hypotension is infrequent. In some patients, the development of optimal blood pressure reduction may require several weeks of therapy. Abrupt withdrawal of enalapril has not been associated with rapid increase in blood pressure.

Effective inhibition of ACE activity normally occurs 2 to 4 hours after oral administration of a single dose of enalapril. Onset of the antihypertensive action was usually seen after one hour with maximum reduction of blood pressure observed 4 to 6 hours after administration. The duration of action is dose-related, but with recommended doses, antihypertensive and haemodynamic effects have been shown to persist for at least 24 hours.

In haemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of enalapril, there was an increase in renal blood flow; glomerular filtration rate was unchanged. There was no evidence of sodium or water retention. However, in patients with low pretreatment glomerular filtration rates, the rates were usually increased.

In short-term clinical studies in diabetic and non-diabetic patients with renal diseases, decreases in albuminuria and urinary excretion of IgG and total urinary protein were seen after the administration of enalapril.

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 the 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.

Lercanidipine

Lercanidipine is a calcium antagonist of the dihydropyridine group and inhibits the transmembrane influx of calcium into cardiac and smooth muscle. The mechanism of the antihypertensive action is based on a direct relaxant effect on vascular smooth muscle, thus lowering total peripheral resistance. Despite its short pharmacokinetic plasma half-life, lercanidipine is endowed with a prolonged antihypertensive activity, because of its high membrane partition coefficient, and is devoid of negative inotropic effects due to its high vascular selectivity.

Since the vasodilatation produced by lercanidipine has a gradual onset, acute hypotension with reflex tachycardia has only been rarely observed in hypertensive patients.

As with other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is mainly due to its (S) enantiomer.

Enalapril/Lercanidipine
The combination of these substances has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.

In a pivotal phase III, double blind, add-on clinical trial conducted in 342 non responders to lercanidipine 10 mg (defined as SDBP 95-114 and SSBP 140-189 mmHg), the reduction in trough SSBP was 5.4 mmHg greater with the combination enalapril 10 mg/lercanidipine 10 mg than with lercanidipine 10 mg alone after 12 weeks of double-blind treatment (-7.7 mmHg vs -2.3 mmHg, p<0.001). Also the reduction in trough SDBP was 2.8 mmHg greater with the combination as compared to the monotherapy (-7.1 mmHg vs -4.3 mmHg, p<0.001).
Responder rates resulted significantly higher with combination therapy than with monotherapy: 41% vs 24% (p< 0.001) for SSBP and 35% vs 24% (p=0.032) for SDBP. A significantly higher percentage of patients on combination treatment experienced normalization of SSBP (39% vs 22%, p<0.001) and of SDBP (29% vs 19%, p=0.023) compared with patients on monotherapy. In the open-label long term follow-up phase of this study a titration to the combination enalapril 20 mg/lercanidipine 10 mg was allowed if BP remained >140/90 mmHg: titration occurred in 133/221 patients and SDBP normalized after titration in 1/3 of these cases.

In a pivotal phase III, double blind, add-on clinical trial conducted in 327 non responders to enalapril 20 mg (defined as SDBP 95-114 and SSBP 140-189 mmHg), patients on enalapril 20 mg/lercanidipine 10 mg achieved a significantly greater reduction in trough SSBP compared with those on monotherapy (-9.8 vs -6.7 mmHg, p=0.013) and in trough SDBP (- 9.2 vs -7.5 mmHg, p=0.015). Responder rates were not significantly higher with combination therapy than with monotherapy (53% vs 43%, p=0.076 for SDBP and 41% vs 33%, p=0.116 for SSBP) and a not significantly higher percentage of patients on combination therapy experienced normalization of SDBP (48% vs. 37%, p=0.055) and of SSBP (33% vs 28%, p=0.325) compared with patients on monotherapy.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

No pharmacokinetic interactions have been observed on concurrent administration of enalapril and lercanidipine.

Pharmacokinetics of enalapril
Absorption

Oral enalapril is rapidly absorbed, with peak serum concentrations of enalapril occurring within one hour. Based on urinary recovery, the extent of absorption of enalapril from oral enalapril maleate is approximately 60%. The absorption of oral enalapril is not affected by the presence of food in the gastrointestinal tract.

Distribution
Following absorption, oral enalapril is rapidly and extensively hydrolysed to enalaprilat, a potent angiotensin-converting enzyme inhibitor. Peak serum concentrations of enalaprilat occur about 4 hours after an oral dose of enalapril maleate. The effective half-life for accumulation of enalaprilat following multiple doses of oral enalapril is 11 hours. In subjects with normal renal function, steady-state serum concentrations of enalaprilat was reached after four days of treatment.
Over the range of concentrations which are therapeutically relevant, enalaprilat binding to human plasma proteins does not exceed 60%.

Biotransformation
Apart from the conversion to enalaprilat, there is no evidence for significant metabolism of enalapril.

Elimination
Excretion of enalaprilat is primarily renal. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and unchanged enalapril (about 20%).

Renal impairment
The exposure of enalapril and enalaprilat is increased in patients with renal insufficiency. In patients with mild to moderate renal insufficiency (creatinine clearance 40-60 ml/min), the steady state AUC of enalaprilat was approximately two-fold higher than in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance  30 ml/min), the AUC was increased approximately 8-fold. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency and time to steady state is delayed (see section 4.2).
Enalaprilat may be removed from the general circulation by haemodialysis. The dialysis clearance is 62 ml/min.

Lactation
After a single 20 mg oral dose in five postpartum women, the average peak enalapril milk level was 1.7µg/L (range 0.54 to 5.9 µg/L) at 4 to 6 hours after the dose. The average peak enalaprilat level was 1.7µg/L (range 1.2 to 2.3µg/L); peaks occurred at various times over the 24-hour period. Using the peak milk level data, the estimated maximum intake of an exclusively breastfed infant would be about 0.16% of the maternal weight-adjusted dosage. A woman who had been taking oral enalapril 10 mg daily for 11 months had peak enalapril milk levels of 2 µg/L 4 hours after a dose and peak enalaprilat levels of 0.75 µg/L about 9 hours after the dose. The total amount of enalapril and enalaprilat measured in milk during the 24 hour period was 1.44µg/L and 0.63 µg/L of milk respectively. Enalaprilat milk levels were undetectable (<0.2µg/L) 4 hours after a single dose of enalapril 5 mg in one mother and 10mg in two mothers; enalapril levels were not determined.

Pharmacokinetics of lercanidipine
Absorption
Lercanidipine is completely absorbed after oral administration and peak plasma levels are reached after approximately 1.5 - 3 hours.

The two enantiomers of lercanidipine show a similar plasma level profile: the time to peak plasma concentration is the same and the peak plasma concentration and AUC are, on average 1.2 times higher for the (S)-enantiomer. The elimination half-lives of the two 

enantiomers are essentially the same. No interconversion of the two enantiomers is observed “in vivo”.

Due to the high first-pass metabolism, the absolute bioavailability of oral lercanidipine in non- fasted conditions is about 10%. However, the bioavailability on ingestion by healthy volunteers under fasting conditions is reduced to 1/3.

Oral availability of lercanidipine increases 4-fold when it is ingested up to 2 hours after a high-fat meal. Hence the drug should be taken before meals.

Distribution
Distribution from plasma into tissues and organs is rapid and extensive.

The degree of plasma protein binding of lercanidipine exceeds 98%. Since plasma protein levels are reduced in patients with severe renal or hepatic dysfunction, the free fraction of the drug may be higher.

Biotransformation
Lercanidipine is extensively metabolised by CYP3A4; no parent substance is found either in urine or faeces. It is predominantly converted into inactive metabolites and approximately 50% of the dose is excreted in the urine.

In vitro experiments with human liver microsomes have demonstrated that lercanidipine shows slight inhibition of the two enzymes CYP3A4 and CYP2D6 at concentrations 160- and 40-times higher than the peak plasma levels achieved after administration of the 20 mg dose.

Furthermore, interaction studies in humans have shown that lercanidipine does not modify the plasma levels of midazolam, a typical substrate of CYP3A4, or of metoprolol, a typical substrate of CYP2D6. Therefore, at therapeutic doses, lercanidipine is not expected to inhibit the biotransformation of drugs metabolised by CYP3A4 or CYP2D6.

Elimination
Elimination essentially occurs through biotransformation.

A mean terminal elimination half-life of 8-10 hours was calculated, and due to the high binding to lipid membranes, therapeutic activity lasts for 24 hours. No accumulation was shown after repeated administration.

Linearity/non-linearity
Oral administration of lercanidipine results in plasma levels that are not directly proportional to the dose (non-linear kinetics). After 10, 20 or 40 mg, peak plasma concentrations were in the ratio of 1:3:8 and areas under the plasma concentration-time curves in the ratio of 1:4:18, suggesting a progressive saturation of first pass metabolism. Accordingly, availability increases with dosage elevation.

Additional information on special populations
It has been shown that the pharmacokinetic behaviour of lercanidipine in elderly patients and in patients with mild to moderate renal dysfunction or mild to moderate hepatic impairment is similar to that observed in the general patient population. Patients with severe renal dysfunction or dialysis-dependent patients showed higher concentrations of the drug (approximately 70%). In patients with moderate to severe hepatic impairment, systemic bioavailability of lercanidipine is probably increased because the drug is normally extensively metabolised in the liver.