HEMODYNAMICS, CARDIAC CONDUCTION AND PHARMACOKINETICS OF MIBEFRADIL (RO-40-5967), A NOVEL CALCIUM-ANTAGONIST

Objectives: Mibefradil (Ro 40-5967) is a chemically novel non-dihydrop yridine calcium antagonist. In this phase II study we compared its acu te and chronic effects on blood pressure, heart rate and atrioventricu lar conduction (electrocardiographic PQ interval) with those of verapa mil and diltiazem. Patients and methods: After a 4-week placebo run-in , 18 patients with mild to moderate essential hypertension were given single doses of mibefradil (150 mg), slow-release (SR) verapamil (240 mg), diltiazem (240 mg) and placebo at weekly intervals; pharmacokinet ics and the effects on blood pressure, heart rate and PQ interval were studied on four 10-h study days. Seventeen of the same patients subse quently underwent 4 weeks of treatment with either mibefradil (100 mg daily; n = 10) or verapamil SR (240 mg daily; n = 7), and on the last day, they attended a further 10-h study day. Two studies were conducte d: an acute, single-dose, double-blind, randomly allocated, placebo-co ntrolled, crossover study and a chronic, open-label, randomly allocate d, parallel-group study. Results: Mibefradil was well tolerated. In th e acute study, the antihypertensive effect (difference from placebo) o f mibefradil 150 mg was of slower onset than that of verapamil or dilt iazem, but comparable blood pressure reductions had been achieved by 6 h. The mean+/-SD maximal PQ prolongation (difference from placebo) wa s 15.6+/-16.1 ms, compared with 44.0+/-22.6 ms for verapamil and 56.0/-48.9 ms for diltiazem (P<0.05 mibefradil versus verapamil; P<0.01 mi befradil versus diltiazem). In the chronic study there were no signifi cant differences during steady-state conditions between mibefradil at 100 mg and verapamil SR at 240 mg in their effects on blood pressure, PQ and heart rate. The mean+/-SD elimination half-life (t(1/2)) of mib efradil under steady-state conditions was 26.8+/-5.5 h (versus an appa rent t(1/2) of 16.9+/-11.1 h for verapamil SR, P<0.05). Conclusions: M ibefradil is a well-tolerated and efficacious antihypertensive agent w ell suited to single daily dosing because of its intrinsic long plasma half-life. The effects on both blood pressure and PQ interval are of more gradual onset than those of unmodified verapamil and diltiazem af ter single doses.