Lercanidipine

Lercanidipine (Zanidip®) is a vasoselective dihydropyridine calcium channel antagonist that causes systemic vasodilation by blocking the influx of calcium ions through L-type calcium channels in cell membranes. It is a highly lipophilic drug that exhibits a slower onset and longer duration of action than other calcium channel antagonists. Furthermore, lercanidipine may have antiatherogenic activity unrelated to its antihypertensive effect.

In two large, nonblind, noncomparative studies involving approximately 16 000 patients with mild-to-moderate hypertension, systolic blood pressure (BP) [SBP] and diastolic BP (DBP) were significantly reduced after 12 weeks' treatment with lercanidipine 10–20 mg/day. Furthermore, in the largest study, 64% of patients were responders (DBP <90mm Hg) after 12 weeks of treatment and an additional 32% had their BP normalised (BP <140/90mm Hg).

In comparative trials, lercanidipine 10–20 mg/day was as effective as nifedipine slow release (SR) 20–40mg twice daily, amlodipine 10 mg/day, felodipine 10–20 mg/day, nifedipine gastrointestinal therapeutic system (GITS) 30–60mg once daily or verapamil SR 240 mg/day at reducing SBP and DBP in patients with mild-to-moderate hypertension after 2–16 weeks of therapy. In addition, 4 weeks of lercanidipine therapy (10 mg/day) was as effective as captopril 25mg twice daily, atenolol 50 mg/day or hydrochlorothiazide 12.5 mg/day.

Lercanidipine 5–30 mg/day effectively decreased BP in elderly patients (aged >60 years) with mild-to-moderate hypertension or isolated systolic hypertension to the same extent as amlodipine 5–10 mg/day, nifedipine GITS 30–60 mg/day or lacidipine 2–4 mg/day after 24–26 weeks of therapy. In addition, a limited number of studies suggest that lercanidipine may have antihypertensive efficacy in patients with severe or resistant hypertension, in hypertensive patients with type 2 diabetes mellitus and in postmenopausal women with mild-to-moderate essential hypertension.

Lercanidipine is well tolerated, with most treatment-emergent events related to vasodilation. Common adverse events included headache, flushing and peripheral oedema. Importantly, the incidence of vasodilatory oedema was significantly lower in patients receiving lercanidipine than in those receiving some other calcium channel antagonists.

Lercanidipine is a third-generation dihydropyridine calcium channel antagonist, that blocks calcium entry into smooth muscle cells, thereby causing peripheral vasodilation and a reduction in blood pressure (BP).

The antihypertensive effect of lercanidipine is gradual in onset and long in duration (mean time to equilibrium effect was 70–116 minutes at log⁻⁷ to log⁻¹⁰ concentrations). Significant reductions in BP were maintained over a 24-hour period in patients with essential hypertension who received lercanidipine 10 or 20 mg/day.

Lercanidipine is vasoselective and has little cardiodepressant activity. Heart rate or electrocardiographic parameters were not significantly altered in clinical trials in patients with hypertension. In small studies, left ventricular mass was significantly reduced compared with baseline in patients with hypertension treated with lercanidipine 10 mg/day for up to 12 months.

Lercanidipine has an antiatherogenic effect unrelated to its antihypertensive activity. Studies in patients with hypertension with or without type 2 diabetes mellitus have shown that lercanidipine also has antioxidant activity. Lercanidipine 10 mg/day for 16 weeks significantly reduced low-density lipoprotein cholesterol oxidation in patients with hypertension and type 2 diabetes.

Lercanidipine appears to neutrally or favourably affect lipid and glucose metabolism in patients with hypertension. As with other calcium channel antagonists, no significant effect on the albumin/creatinine ratio was seen in patients with hypertension and type 2 diabetes treated with lercanidipine for 16 weeks. In addition, creatinine clearance, but not plasma creatinine concentrations, increased by 10% compared with baseline in patients with chronic renal failure.

Lercanidipine is administered as a racemic mixture. The mean maximum plasma concentration (C_max) of S-lercanidipine after a single oral dose of lercanidipine 10 or 20mg in patients with mild-to-moderate hypertension was 1.75 and 4.09 μg/L and time to C_max was 2.3 and 3.3 hours; the corresponding mean area under the plasma concentration-time curve (AUC) was 4.55 and 16.36 μg ⋅ h/L indicating a non-linear profile. Lercanidipine is highly bound to plasma proteins (>98%).

After absorption, oral lercanidipine undergoes extensive first-pass metabolism, with approximately equivalent amounts of an oral dose eliminated in the urine and the faeces as metabolites. In patients with hypertension or angina pectoris, the mean terminal elimination half-life in plasma for a single oral dose of lercanidipine 10 or 20mg was 8 or 10.5 hours.

The pharmacokinetic profile of lercanidipine in elderly patients or patients with mild hepatic impairment or mild-to-moderate renal impairment is not significantly different from that of otherwise healthy patients with hypertension. However, accumulation of lercanidipine occurred after repeat administrations in patients with severe renal impairment.

Coadministration of lercanidipine with inhibitors of the cytochrome P450 (CYP) 3A4 (e.g. ketoconazole) led to significantly increased lercanidipine C_max (8-fold) or AUC values (15-fold). Furthermore, in vivo coadministration of lercanidipine and midazolam, a substrate of CYP3A4, did not alter the plasma concentrations of midazolam, but increased the extent (by ≈40%) and decreased the rate (by ≈75%) of lercanidipine absorption.

No clinically significant interactions were reported when lercanidipine 10 or 20 mg/day was coadministered with β-methyldigoxin, cimetidine at standard dosages, simvastatin 40mg, sildenafil, warfarin, diuretics or ACE inhibitors.

Systolic BP (SBP) was significantly reduced from baseline by 19 and 26mm Hg and diastolic BP (DBP) by 13 and 15mm Hg after 12 weeks of therapy with lercanidipine 10–20 mg/day in two large noncomparative studies involving 16 105 patients with grade 1, 2 or 3 hypertension. Reductions in BP were similar in those receiving lercanidipine monotherapy and those receiving combination therapy with other antihypertensive agents in one trial. Furthermore, in one study (ELYPSE [Eficacia de Lecanidipino y su Perfil de Seguridad]) 64% of patients were responders (DBP <90mm Hg) after 12 weeks of treatment and 32% had their BP normalised (BP <140/90mm Hg).

Compared with other calcium channel antagonists, lercanidipine 10–20 mg/day was as effective as nifedipine slow release (SR) 20–40mg twice daily, amlodipine 10 mg/day, felodipine 10–20 mg/day, nifedipine gastrointestinal therapeutic system (GITS) 30–60mg once daily or verapamil SR 240 mg/day at reducing SBP and DBP in patients with mild-to-moderate hypertension after 2–16 weeks of therapy. Furthermore, 4 weeks of lercanidipine therapy (10 mg/day) was also as effective as captopril 25mg twice daily, atenolol 50 mg/day or hydrochlorothiazide 12.5 mg/day at reducing BP in patients with mild-to-moderate hypertension. Normalisation rates were higher at completion of therapy than after 4 weeks in studies which employed dosage titration in nonresponders after 4 weeks.

In one study, lercanidipine monotherapy reduced BP in patients with severe hypertension, albeit at dosages higher than those currently recommended. As add-on therapy, lercanidipine 10–30 mg/day was as effective as nitrendipine 10–30 mg/day in patients with hypertension not responding to therapy with other antihypertensive agents.

Lercanidipine 5–30 mg/day decreased BP in elderly patients (aged >60 years) with mild-to-moderate hypertension or isolated systolic hypertension to a similar extent to amlodipine 5–10 mg/day, nifedipine GITS 30–60 mg/day or lacidipine 2–4 mg/day after 24–26 weeks of therapy.

Lercanidipine has also demonstrated antihypertensive efficacy in patients with type 2 diabetes and in postmenopausal women with mild-to-moderate essential hypertension in single studies.

Lercanidipine was well tolerated in clinical trials with most treatment-emergent adverse events related to vasodilation. In the two largest studies, involving 16 105 patients with mild-to-moderate hypertension, adverse events were observed in 1.6 and 6.5% of patients receiving lercanidipine 10 or 20 mg/day. Headache (0.2% and 2.9%), ankle oedema (0.4% and 1.2%) and flushing (1.0% and 1.1 %) were the most commonly reported events.

Adverse events were reported in 11.8% of lercanidipine recipients (10 or 20mg once daily) compared with 7.0% of those receiving placebo in a pooled analysis of data from 20 clinical trials involving almost 1800 patients with hypertension. Similar percentages of patients withdrew because of poor tolerability (5% and 3%) and the most commonly reported events were headache, flushing, vertigo, palpitations and ankle oedema.

Lercanidipine was well tolerated in elderly patients (aged >60 years) during both short-term (8–24 weeks) and longer-term treatment (>6 months). Adverse events, including peripheral oedema, elevated liver enzymes, flushing and headache were reportedby <3–19.4% of elderly patients receiving lercanidipine 10 or 20 mg/day. A small number of elderly lercanidipine recipients withdrew because of poor tolerability.

Lercanidipine 10 or 20 mg/day showed a similar tolerability profile to captopril 50–100 mg/day, atenolol 50–100 mg/day and losartan 50–100 mg/day. However, adverse events were less common with lercanidipine 10–20mg once daily than with nitrendipine (10 or 20 mg/day), nifedipine SR (20–40 mg twice daily) and nifedipine GITS (30–60 once daily) during 8–24 weeks of therapy. The incidence of peripheral oedema was significantly lower during treatment with lercanidipine 10–20 mg/day than during treatment with amlodipine or nifedipine GITS, whereas treatment withdrawals due to peripheral oedema were similar in patients treated with lercanidipine 10–20 mg/day or lacidipine 2–4 mg/day.

Furthermore, patients reported significantly fewer adverse events after switching to lercanidipine from amlodipine, nifedipine GITS, felodipine or nitrendipine. The incidence of oedema was reduced by 46%, flushing by 51 % and headache and rash both by 53% (p < 0.001 for all comparisons).

Oral lercanidipine is approved for the treatment of mild-to-moderate hypertension in most of Europe (including the UK), Asia, Australasia and South America. UK prescribing information indicates that lercanidipine therapy should be initiated at 10 mg/day. The dosage can be gradually titrated to 20 mg/day in patients who do not respond satisfactorily.

Dosage adjustments are not required in the elderly or in patients with mild-to-moderate renal or hepatic dysfunction. Lercanidipine is not recommended for use in patients with severe hepatic or renal dysfunction, nor in patients aged <18 years.

Lercanidipine is contraindicated during pregnancy and lactation, in women of child-bearing potential unless effective contraception is used, in patients with left ventricular outflow tract obstruction, untreated congestive heart failure, unstable angina pectoris or within 1 month of a myocardial infarction.

Lercanidipine should not be coadministered with inhibitors of CYP3A4 or cyclosporin or grapefruit juice. Furthermore, caution should be exercised when administering lercanidipine with inducers or other substrates of CYP3A4. Lercanidipine can be coadministered with warfarin, simvastatin, β-methyldigoxin and low dosages of cimetidine (<-800 mg/day), although patients receiving concomitant digoxin should be monitored for digoxin toxicity.