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 its antihypertensive action is due to 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 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.

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 ⅓ 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, of lercanidipine should be taken before meals. h3. 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 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.

Special populations

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.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

Safety pharmacological studies in animals have shown no effects on the autonomic nervous system, the central nervous system or on gastrointestinal function at antihypertensive doses.

The relevant effects which have been observed in long-term studies in rats and dogs were related, directly or indirectly, to the known effects of high doses of Ca-antagonists, predominantly reflecting exaggerated pharmacodynamic activity.

Lercanidipine was not genotoxic and showed no evidence of carcinogenic hazard.

Fertility and general reproductive performance in rats were unaffected by treatment with lercanidipine.

There was no evidence of any teratogenic effect in rats and rabbits; however, in rats, lercanidipine at high dose levels induced pre- and post-implantation losses and delay in foetal development.

Lercanidipine hydrochloride, when administered at high dose (12 mg/kg/day) during labour, induced dystocia. The distribution of lercanidipine and/or its metabolites in pregnant animals and their excretion in breast milk have not been investigated.

Metabolites have not been evaluated separately in toxicity studies.