Drugs

, Volume 60, Issue 5, pp 1123–1140 | Cite as

Lercanidipine

A Review of its Use in Hypertension
Adis Drug Evaluation

Summary

Abstract

Lercanidipine is a vasoselective dihydropyridine calcium antagonist which causes systemic vasodilation by blocking the influx of calcium ions through L-type calcium channels in cell membranes. It is a highly lipophilic drug and as such has a slower onset and longer duration of action than a number of other calcium antagonists. Preclinical evidence suggests that lercanidipine has anti-atherogenic potential and it may also protect against end-organ damage.

In well controlled clinical studies, once daily administration of lercanidipine 10 or 20mg effectively reduced blood pressure (BP) compared with placebo in patients with mild to moderate hypertension without affecting heart rate. Response rate (percentage of patients with diastolic BP ≤90mm Hg or reduced by ≥10mm Hg from baseline) ranged from 50 to 66% with lercanidipine 10 mg/day and up to 86% with lercanidipine 20 mg/day. The drug had a long duration of action: clinical measurements for diastolic BP yielded a trough/peak ratio of ≥0.8 for both lercanidipine dosages in 1 study. Comparative trials, either published in full or as abstracts, found lercanidipine 10mg once daily for ≥4 weeks to be at least as effective as atenolol 50mg once daily, candesartan cilexetil 16 mg/day, captopril 25mg twice daily, enalapril 20 mg/day, hydrochlorothiazide 12.5mg once daily, irbesartan 150 mg/day and slow release nifedipine 20mg twice daily in patients with mild to moderate hypertension. In addition, lercanidipine 20 mg/day was as effective as amlodipine 10 mg/day.

Lercanidipine is effective in the treatment of elderly patients (aged 60 to 85 years) with mild to moderate essential hypertension and in those with isolated systolic hypertension. In addition, monotherapy with lercanidipine 20 or 40 mg/day has shown efficacy in patients with severe hypertension, and add-on therapy helped control BP in a large proportion of patients with severe hypertension not responding sufficiently to β-blockers, diuretics or ACE inhibitors. Unpublisheddata indicate that the drug reduces blood pressure in patients with type 2 (non-insulin-dependent) diabetes mellitus, without adversely affecting glucose homeostasis.

Lercanidipine was well tolerated in clinical trials, with most treatment-related adverse events typical of dihydropyridine calcium antagonists, namely headache, flushing, dizziness and ankle oedema.

Conclusions: Lercanidipine is an effective and well tolerated once daily antihypertensive agent in patients with mild to moderate hypertension. In addition, the drug may reduce BP when used as monotherapy in patients with severe hypertension or when used adjunctively in patients with resistant hypertension. Importantly, lercanidipine appears to be at least as effective and well tolerated as other commonly used antihypertensive agents. The drug therefore represents a useful therapeutic option in the management of patients with hypertension and will be particularly useful in patients not responding to, or intolerant of, anti-hypertensive agents from other drug classes.

Pharmacodynamic Properties

Lercanidipine is a third generation dihydropyridine calcium antagonist with a bulky bis-phenylalkylamine side chain. The drug reversibly blocks voltage-dependent Ca2+ influx through L-type channels in cell membranes, and the subsequent peripheral vasodilation leads to a reduction in blood pressure (BP).

Lercanidipine is highly lipophilic, and as such has a slower onset and longer duration of action than a number of other drugs in its class. Furthermore, the drug is vasoselective and has shown less in vitro and in vivo negative inotropic activity than some other dihydropyridines, including nitrendipine and felodipine.

Results from preclinical studies indicate that lercanidipine has antiatherogenic potential independent of its BP-lowering effects, and may protect against end-organ damage. Importantly, the drug does not interfere with normal cardiac excitation and conduction when used at therapeutic dosages in patients with hypertension.

Pharmacokinetic Properties

Maximum plasma concentrations (Cmax) of S-lercanidipine, the enantiomer responsible for the activity of racemic lercanidipine were reached ≈2 to 3 hours after oral administration of lercanidipine 10 or 20mg in 12 patients with mild to moderate hypertension. Plasma levels and the area under the plasma concentration-time curve (AUC) were not linearly related to dose, indicating saturable metabolism.

The presence of food increases lercanidipine absorption, hence the recommendation that lercanidipine be taken before meals.

Once absorbed, the drug readily accumulates in the lipid bilayer of cell membranes in the arterial wall because of its bulky bis-phenyl side chain. The drug is highly (>98%) bound to plasma proteins.

After oral administration lercanidipine undergoes extensive first-pass metabolism (primarily by cytochrome P450 3A4) to largely inactive metabolites. =50% of an oral dose of [14C]lercanidipine was eliminated in faeces and 44% in urine (mostly as metabolites). The drug appears to have a biphasic elimination profile, with terminal elimination half-lives of 2.8 to 3.7 hours (first phase) and 10.5 hours.

The bioavailability of S-lercanidipine after oral lercanidipine is not affected by age or cirrhosis but accumulation has been reported in patients with severe renal dysfunction. Dosage reduction is therefore recommended in this patient group.

No significant pharmacokinetic interactions have been reported between lercanidipine and midazolam, metoprolol, cimetidine or metildigoxin.

Therapeutic Efficacy

Lercanidipine 5 to 20mg once daily for 4 weeks dose-dependently and significantly reduced trough diastolic blood pressure (DBP) compared with placebo in patients with mild to moderate hypertension, without affecting heart rate. Response rates (percentage of patients with DBP ≤90mm Hg or reduced from baseline by ≥10mm Hg) ranged from 50 to 66% with lercanidipine 10 mg/day and up to 86% with lercanidipine 20 mg/day. The effects of lercanidipine 10 and 20mg were sustained throughout the 24-hour dosage interval; 1 study found that both dosages yielded a DBP trough/peak ratio >0.8.

Published studies (or abstracts) have shown that lercanidipine 10mg once daily for ≥4 weeks is at least as effective in patients with mild to moderate essential hypertension as a number of other antihypertensive drugs, including atenolol 50mg once daily, candesartan cilexetil 16 mg/day, captopril 25mg twice daily, enalapril 20 mg/day, hydrochlorothiazide 12.5mg once daily, irbesartan 150 mg/day and slow release nifedipine 20mg twice daily. A higher dosage (lercanidipine 20 mg/day) had antihypertensive efficacy similar to that of amlodipine 10 mg/day. Studies of lercanidipine 10mg once daily which permitted dosage titration to lercanidipine 20mg once daily after 4 weeks in nonresponders found that normalisation rates were higher at week 8 than week 4.

Monotherapy with lercanidipine 20 or 40 mg/day effectively reduced BP in the majority of patients with severe hypertension in 1 study. Furthermore, lercanidipine 10 to 30 mg/day was effective add-on therapy in patients with hypertension not responding sufficiently to β-blockers, diuretics or ACE inhibitors.

Lercanidipine is effective in the treatment of mild to moderate essential hypertension or isolated systolic hypertension in elderly patients (aged 60 to 85 years). The drug also demonstrated antihypertensive efficacy in patients with type 2 (non-insulin-dependent) diabetes mellitus but these data have yet to be published.

Tolerability|

Lercanidipine was well tolerated in clinical trials, with most treatment-emergent adverse events related to vasodilation. A pooled analysis of data from 20 clinical trials involving almost 1800 patients with hypertension found that 11.8% of lercanidipine 10 or 20mg once daily recipients compared with 7.0% of placebo recipients reported adverse events, the most common being headache, flushing, asthenia, vertigo, palpitations and ankle oedema. Approximately 5 and 3% of patients in the respective groups withdrew because of poor tolerability.

Two postmarketing surveillance studies involving a total of 9605 patients with hypertension have confirmed that lercanidipine is well tolerated in clinical practice.

Evidence suggests that the drug is well tolerated in the elderly, and when administered long term (1 year). In addition, the drug was well tolerated with regard to ECG parameters in clinical trials.

Comparative trials have shown that lercanidipine 10 or 20 mg/day is as well tolerated as captopril 50 to 100 mg/day and atenolol 50 or 100 mg/day, although the tolerability profiles of these agents differed slightly.

An abstract report of a study in patients who had reported adverse vasodilatory effects while taking amlodipine, nifedipine GITS (gastrointestinal therapeutic system), felodipine or nitrendipine showed that, after switching to lercanidipine 10 to 20 mg/day for 1 month, the prevalence of calf oedema (from 94.8 to 51.4%), headache (from 38 to 18%), flushing (from 35 to 17%) and skin rash (from 38 to 18%) decreased significantly.

Dosage and Administration

Oral lercanidipine is indicated in Europe for the treatment of mild to moderate hypertension for which the recommended initial dosage is 10mg once daily at least 15 minutes before meals. In patients with an initial unsatisfactory response, dosage titration to 20 mg/day should be done gradually.

Special care should be exercised when initiating treatment with lercanidipine in the elderly or patients with mild to moderate renal or hepatic dysfunction, although dosage adjustments are not required in such patients. Use of lercanidipine is contraindicated in patients with severe hepatic or renal (creatinine clearance <10 ml/min).

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© Adis International Limited 2000

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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