Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Selective calcium channel blockers with mainly vascular effects – Dihydropyridine derivatives
ATC code: C08CA13

Mechanism of action
Lercanidipine is a calcium antagonist of the dihydropyridine group and inhibits the transmembrane influx of calcium into cardiac and smooth muscle. The mechanism of its antihypertensive action is due to a direct relaxant effect on vascular smooth muscle thus lowering total peripheral resistance.

Pharmacodynamic effects
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 induced by lercanidipine is gradual in onset, acute hypotension with reflex tachycardia has rarely been observed in hypertensive patients.
As for other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is mainly due to its (S)-enantiomer.

Clinical efficacy and safety
The clinical efficacy and safety of lercanidipine at a dose of 10-20 mg once daily has been evaluated in double-blind, placebo-controlled clinical trials (with 1200 patients receiving lercanidipine and 603 patients receiving placebo) and in active-controlled and uncontrolled long term clinical trials on a total of 3676 hypertensive patients.
Most clinical trials have been conducted in patients with mild to moderate essential hypertension (including elderly and diabetic patients), receiving lercanidipine alone or in combination with ACE-Is, diuretics or beta- blockers.

In addition to the clinical studies conducted to support the therapeutic indications, a further small uncontrolled but randomised study of patients with severe hypertension (mean ± SD diastolic blood pressure of 114.5 ± 3.7 mmHg) showed that blood pressure was normalised in 40% of the 25 patients on 20 mg once daily dose and in 56% of 25 patients on 10 mg twice daily doses of lercanidipine. In a double-blind, randomized, controlled study versus placebo in patients with isolated systolic hypertension lercanidipine was efficacious in lowering systolic blood pressure from mean initial values of 172.6 ± 5.6 mmHg to 140.2 ± 8.7 mmHg.
No clinical trial has been performed in the paediatric population.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
Lercanidipine is completely absorbed after 10-20 mg oral administration and peak plasma levels, 3.30 ng/ml ± 2.09 s.d. and 7.66 ng/ml ± 5.90 s.d. respectively, occur about 1.5-3 hours after dosing.
The two enantiomers of lercanidipine show a similar plasma level profile: the time to peak plasma concentration is the same, the peak plasma concentration and AUC are, on average, 1.2-fold higher for the (S) enantiomer and the elimination half-lives of the two enantiomers are essentially the same. No “in vivo” interconversion of enantiomers is observed.
Due to the high first pass metabolism, the absolute bioavailability of lercanidipine orally administered to patients under fed conditions is around 10%, although it is reduced to 1/3 when administered to healthy volunteers under fasting conditions.
Oral availability of lercanidipine increases 4-fold when lercanidipine is ingested up to 2 hours after a high fat meal. Accordingly, Vasodip should be taken before meals.
Distribution
Distribution from plasma to tissues and organs is rapid and extensive.
The degree of serum 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 increased.



Biotransformation
Lercanidipine is extensively metabolised by CYP3A4, no parent drug is found in the urine or the faeces. It is predominantly converted to inactive metabolites and about 50% of the dose is excreted in the urine.
“In vitro" experiments with human liver microsomes have demonstrated that lercanidipine shows some degree of inhibition of CYP3A4 and CYP2D6, at concentrations 160- and 40-fold, respectively, higher than those reached at peak in the plasma after the dose of 20 mg.
Moreover, interaction studies in humans have shown that lercanidipine did not modify the plasma levels of midazolam, a typical substrate of CYP3A4, or of metoprolol, a typical substrate of CYP2D6. Therefore, inhibition of biotransformation of drugs metabolised by CYP3A4 and CYP2D6 by lercanidipine is not expected at therapeutic doses.
Elimination
Elimination occurs essentially by biotransformation.
A mean terminal elimination half-life of 8-10 hours was calculated and the therapeutical activity lasts for 24 hours because of its high binding to lipid membrane. No accumulation was seen upon repeated administration.
Linearity/non-linearity
Oral administration of lercanidipine leads to plasma levels of lercanidipine not directly proportional to dosage (non-linear kinetics). After 10, 20 or 40 mg, peak plasma concentrations observed were in the ratio 1:3:8 and areas under plasma concentration time curves in the ratio 1:4:18, suggesting a progressive saturation of first pass metabolism. Accordingly, availability increases with dosage elevation.
Additional information on special population
In elderly patients and in patients with mild to moderate renal dysfunction or mild to moderate hepatic impairment the pharmacokinetic behaviour of lercanidipine was shown to be similar to that observed in the general patient population; patients with severe renal dysfunction or dialysis-dependent patients showed higher levels (about 70%) of the drug. In patients with moderate to severe hepatic impairment, the systemic bioavailability of lercanidipine is likely to be increased since the drug is normally metabolised extensively in the liver.