Pharmacokinetic and pharmacodynamic properties of a new controlled-release formulation of metoprolol: A comparison with conventional tablets

Abstract

The pharmacokinetic and pharmacodynamic properties of a new multiple-unit, controlled-release (CR) formulation of metoprolol (metoprolol succinate, 95 mg once daily), which has almost constant (zero-order) release properties over most of a 24-h dose interval, have been compared with those of conventional metoprolol tablets (metoprolol tartrate, 100 mg once daily and 50 mg twice daily), in 12 healthy male volunteers. The steady-state plasma concentrations of metoprolol after five days of treatment varied less throughout the day with the CR than with the conventional formulation. This was associated with a considerably lower peak plasma concentration and the achievement of a significantly higher plasma concentration at the end of the dose interval. Similarly, the effect on exercise-induced tachycardia was maintained at a relatively constant level throughout the day after treatment with the CR formulation. A significantly greater effect 24 h after administration was achieved with the CR formulation, when compared with once-daily dosing with metoprolol tablets, 100 mg. Twice-daily dosing with metoprolol tablets, 50 mg, produced a similar beta 1-blocking effect at the end of the dose interval to that observed with metoprolol CR. Although the steady-state plasma concentrations indicated significantly lower systemic availability for the CR formulation, compared with both regimens of metoprolol tablets, the total effect over the dose interval, expressed as the area under the efficacy curve (AUEC), was similar for the three treatments. The relationship between steady-state plasma concentrations and the pharmacodynamic efficacy at corresponding times, indicated that plasma concentrations were more effectively utilized after the administration of the CR formulation than after the conventional tablet regimens.(ABSTRACT TRUNCATED AT 250 WORDS)

β-Adrenergic Receptor Blockade in Chronic Heart Failure

“…38 The MERIT-HF trial enrolled 3991 subjects with ischemic and nonischemic dilated cardiomyopathies who had class II through IV heart failure 38 ; the metoprolol preparation used was a continuous release (CR), single-daily-dose formulation of coated metoprolol succinate pellets. 79 Importantly, the average dose of metoprolol achieved in MERIT-HF was larger than in MDC, 159 versus 108 mg. Most subjects (97%) enrolled in MERIT-HF were categorized as class II or III heart failure, and on the basis of the annualized mortality of 11% in the placebo group and the baseline left ventricular ejection fraction of 28%, this landmark clinical trial enrolled subjects with mild to moderate heart failure and moderate to severe systolic dysfunction.…”

“…79 The bioavailability of the CR preparation is Ϸ70% of the conventional formulation. 77 However, compared with 50 mg BID of the conventional formulation, 100 mg of the CR preparation produces similar trough levels and degrees of reduction in exercise heart rate, indicating bioequivalence of the 2 preparations.…”

“…77 However, compared with 50 mg BID of the conventional formulation, 100 mg of the CR preparation produces similar trough levels and degrees of reduction in exercise heart rate, indicating bioequivalence of the 2 preparations. 79 The reduced fluctuation in blood levels for the CR compared with the conventional formulation provides the potential for improved tolerability of the CR formulation in heart failure patients, but no direct comparison studies have been performed. In addition, the much more shallow slope of the CR plasma concentration curve at the end of the dosing interval would theoretically reduce the potential of producing a ␤-blocker withdrawal effect 80 if doses are missed or dosing intervals are prolonged.…”

Carvedilol but Not Metoprolol Reduces β-Adrenergic Responsiveness After Complete Elimination From Plasma In Vivo

“…Plasma levels during carvedilol and metoprolol treatment and elimination half-life of carvedilol were in agreement with previously published reports. 14,17 At these concentrations, metoprolol blocks Ϸ50% of ␤ 1 -ARs but Ͻ5% of ␤ 2 -ARs, whereas carvedilol blocks Ͼ90% of both ␤ 1 -and ␤ 2 -ARs. 7 However, because metoprolol displays higher inverse agonist activity than carvedilol, 6,7 these concentrations reduced contractile force in human myocardium by similar extents (43% and 32%, respectively 7 ).…”

Treatment with β‐blockers—the value of an even plasma concentration over 24 h

“…Good tolerability would be expected because metoprolol is a 1 selective -blocker and the peak plasma concentrations in individuals taking metoprolol CR/ZOK are low (14)(15). Further clinical trials have demonstrated a low incidence of adverse effects (16).…”