Pharmacokinetic Considerations of Formulation: Extended-Release Metoprolol Succinate in the Treatment of Heart Failure

Abstract

Extended-release (ER) metoprolol succinate is a controlled-release formulation designed to deliver metoprolol succinate at a near constant rate for approximately 20 h, independent of food intake and gastrointestinal pH. Once-daily dosing of ER metoprolol succinate 12.5–200 mg produces even plasma concentrations over a 24-h period, without the marked peaks and troughs characteristically observed with the immediate-release (IR) formulation. This leads to consistent β₁-blockade over 24 h, while maintaining cardioselectivity at doses up to 200 mg daily. Pharmacokinetic studies have also been performed in heart failure patients and have demonstrated that ER metoprolol succinate is associated with a more pronounced and even β₁-blockade over a 24-h period than the IR formulation. The efficacy and good tolerability of ER metoprolol succinate in heart failure patients has now been demonstrated in a large-scale clinical trial.

Metoprolol, a cardioselective β-blocker lacking intrinsic sympathomimetic activity, has been available in an immediate-release (IR) formulation since 1975 (¹). Similar to other IR drugs, plasma concentrations are characterized by relatively high peaks followed by low troughs. After administration of metoprolol IR 50 mg twice daily to healthy volunteers, the mean peak plasma concentration was 388 n M and the mean trough concentration was 75 n M at steady state (²). Peak plasma concentrations usually occur within 2 h of administration, and trough concentrations follow within 6–12 h. The half-life of metoprolol is 3–7 h (³). Both high peaks and low troughs are undesirable. Abrahamsson et al. investigated the relationship between plasma concentrations of metoprolol and β-blockade as determined by reduction in exercise heart rate (EHR) in healthy volunteers and showed that there is a flat dose response to increasing plasma concentrations of metoprolol above that achieving maximum β₁-blockade. Other key findings were as follows: The theoretical maximal reduction in EHR is 28.3%; however, in practice the maximal reduction is about 25%. Concentrations of metoprolol >300 n M have little extra effect; half of the maximal effect is achieved at metoprolol concentrations of approximately 89 n M. Therefore, a therapeutic level of β-blockade is achieved when plasma concentrations are in the range 80–300 n M. Higher concentrations produce more β₂-blockade (⁴) but little additional β₁-blockade; lower concentrations may result in suboptimal β₁-blockade.

To meet the need for effective and well-tolerated β₁-blockade an extended-release formulation, extended-release (ER) metoprolol succinate was developed with the goal of providing once-daily dosing that maintains therapeutic plasma concentrations and avoids the extreme peaks and troughs characteristic of metoprolol IR (^3,5,6).

Improving the metoprolol formulation: extended-release metoprolol succinate tablets

ER metoprolol succinate (Toprol-XL; AstraZeneca) contains metoprolol succinate in the form of several hundred individual drug delivery units (Fig. 1) (^5,6). The solubility profile of the succinate salt is more suitable for an ER preparation than a tartrate salt. Therefore, the succinate salt was used in the ER formulation in place of the tartrate salt used in the metoprolol IR formulation (^2,5,6). Each microcapsule acts as a diffusion cell designed to deliver metoprolol succinate at a near constant rate for approximately 20 h independent of food intake, pH, and other physiologic factors such as peristalsis (^5,6). The consistent delivery system of once-daily ER metoprolol succinate reduces the peak-to-trough variability observed when subjects take the IR form of metoprolol. When first marketed, ER metoprolol succinate was only manufactured as 50-, 100-, and 200-mg tablets; however, a new 25-mg scored (dividable) tablet has been developed and introduced to the market to facilitate initiation and uptitration in patients with heart failure.

FIG. 1.: Several hundred coated pellets are contained within each extended-release metoprolol succinate tablet. Reproduced with permission from Wikstrand (⁸).

Studies in healthy volunteers that have compared the pharmacokinetic and pharmacodynamic properties of metoprolol IR and ER metoprolol succinate reveal that the ER formulation is associated with a lower maximum plasma concentration (C_max), a higher minimum concentration (C_min), and a lower peak-to-trough fluctuation compared with the IR formulation (^2,7). Sandberg et al. (²) demonstrated that the plasma concentration fluctuation at steady state was 79% for ER metoprolol succinate 100 mg once daily, 470% for metoprolol IR 100 mg once daily, and 225% for metoprolol IR 50 mg twice daily. The same study reported a considerably lower C_max for ER metoprolol succinate 100 mg once daily (163 n M) compared with that of metoprolol IR 100 mg once daily (722 n M) and metoprolol IR 50 mg (388 n M) twice daily. The relatively higher C_max of both doses of metoprolol IR contributed to increased systemic availability as determined by the area under the plasma concentration curve (AUC). The AUC for 50 mg IR twice daily (4,532 nmol h/l) and 100 mg IR once daily (4,645 nmol h/l) were much greater than that of ER metoprolol succinate 100 mg once daily (3068 nmol h/l). However, because of the flat response curve there was no associated decrease in pharmacodynamic effect with the ER preparation; in fact, the total pharmacodynamic effects (i.e., percent reductions in EHR vs time) over the dosing interval were similar for each treatment. Additionally, reductions in EHR reported at various times throughout the dosing interval varied more with metoprolol IR than with ER metoprolol succinate (²).

Similar findings were described by a later study that compared once-daily ER metoprolol succinate 50 mg and once-daily metoprolol IR 50 mg. Results showed the fluctuation index (69%) and the C_max (71 n M) of ER metoprolol succinate were significantly lower than the fluctuation index (529%) and C_max (221 n M) of metoprolol IR (⁷). In addition, the C_min of ER metoprolol succinate (39 n M) was significantly higher than that of metoprolol IR (6 n M). Over 24 h, ER metoprolol succinate produced more consistent plasma levels and more consistent β₁-blockade, as measured by reduction in EHR (Fig. 2) (⁷). The total β-blocking effect of metoprolol IR fluctuated 0.4–19.1%, whereas that of ER metoprolol succinate only fluctuated between 9.0–13.6%. Considering the well-known increase in heart rate and risk of cardiac events during the early morning hours, stable plasma concentrations resulting in consistent β₁-blockade may be of particular importance during this period (^8,9). In a recent comparison between ER metoprolol succinate and metoprolol IR, heart rate during the hour between 4 and 5 am was 55 ± 13 (metoprolol IR 50 mg three times daily), 51 ± 7.9 (ER metoprolol succinate 100 mg once daily), and 49 ± 5.8 beats/min (ER metoprolol succinate 200 mg once daily) (¹⁰).

FIG. 2.: Permission to use this figure has not been granted for online use.

Maximal β₁-blockade is attained at plasma metoprolol concentrations <300–400 n M; plasma concentrations that exceed this level do not produce a greater therapeutic effect but do lead to an increased incidence of adverse events and the loss of β₁-selectivity (^4,11). Metoprolol is primarily metabolized by CYP2D6, an enzyme inhibited by many drugs. Coadministration of these CYP2D6 inhibitors with metoprolol will result in severalfold increases in metoprolol blood levels, which, depending on the dose given, may result in diminished cardioselectivity. However, compared with metoprolol IR, ER metoprolol succinate administration results in plasma levels with lower peaks (peak plasma levels following once-daily administration of ER metoprolol succinate average one fourth to one half the peak plasma levels following a corresponding dose of conventional metoprolol), and therefore, even in the presence of CYP2D6 inhibitors, is less likely to achieve plasma levels at which cardioselectivity is significantly reduced. The maximum plasma concentration of metoprolol IR 100 mg has been reported to range from 722–1,123 n M (^2,12), whereas that of ER metoprolol succinate 200 mg is approximately 284 n M (note this is a plasma concentration that provides almost maximal β₁-blockade) (¹²). A low, yet effective, and more consistent plasma level is desirable and may be especially important in patients with heart failure. These patients develop neurohormonal responses, including increased norepinephrine concentrations, that compensate for the failing heart, and the initiation of β-blockers cause an acute reduction of this adrenergic support. Therefore, theoretically, a lower and more even plasma concentration may allow for a less dramatic reduction in this adrenergic support. In addition, unopposed β₂-mediated vasodilation with the use of a β₁-selective blocker, such as metoprolol, maintains the necessary adrenergic support and may enhance tolerability, particularly during treatment initiation (¹³).

Extended-release metoprolol succinate: pharmacokinetics in patients with heart failure

Prior to the MERIT-HF study (Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure), all studies of metoprolol in patients with heart failure had been performed with metoprolol IR tablets, administered most frequently at a target dose of 50 mg three times daily (^14,15). This three-times-daily treatment schedule was compared with once-daily ER metoprolol succinate 100 mg and 200 mg in a 3-week crossover study of patients with heart failure (n = 15) (^8,10). The plasma concentration curves of ER metoprolol succinate in heart failure patients are comparable to those obtained in healthy subjects (^10,16,17). The pharmacokinetic and pharmacodynamic properties of metoprolol IR and ER metoprolol succinate were analyzed after repeated dosing to steady state. Median plasma concentrations over 24 h for the three different treatment regimens are shown in Fig. 3. Peak plasma concentrations of metoprolol were similar in patients treated with ER metoprolol succinate 200 mg once daily (306 ± 215 n M) and those treated with metoprolol IR 50 mg three times daily (298 ± 183 n M). However, the trough concentration of those treated with ER metoprolol succinate 200 mg once daily (145 ± 124 n M) was substantially higher than that of metoprolol IR 50 mg three times daily (78 ± 76 n M). The peak and trough concentrations of ER metoprolol succinate 100 mg were 133 ± 113 n M and 64 ± 57 n M, respectively. Thus, more favorable trough-to-peak ratios were observed with ER metoprolol succinate compared with metoprolol IR 50 mg three times daily.

FIG. 3.: Median plasma concentration showing peak and trough variability during steady state after intake of immediate-release (IR) metoprolol 50 mg three times daily, extended-release (ER) metoprolol succinate 100 mg once daily, and ER metoprolol succinate 200 mg once daily in 15 patients with congestive heart failure. CR/XL = ER metoprolol succinate. Reproduced with permission from Wikstrand (⁸).

Over 24 h, a more pronounced and more efficient β₁-blockade was observed with once-daily ER metoprolol succinate compared with metoprolol IR 50 mg three times daily. The average heart rate was significantly lower with ER metoprolol succinate 200 mg than with metoprolol IR 50 mg (difference −3.8 beats/min, 95% CI −7.6 to −0.04; p = 0.048) and a greater difference was observed in maximal heart rate over 24 h (−13.6 beats/min, 95% CI −21.1 to −6.1; p = 0.002) (¹⁰). Although comparable β₁-blockade can be achieved with once-daily ER metoprolol succinate and three-times-daily metoprolol IR, in clinical practice metoprolol IR is typically administered twice daily, a regimen that can be expected to produce more variable β₁-blockade and intermittent β₂-blockade. Even when metoprolol IR is given three times daily, the plasma concentration at trough is significantly lower than the trough plasma concentration seen with metoprolol succinate. The ratio of plasma concentrations at trough (ER metoprolol succinate 200 mg/IR metoprolol tartrate 50 mg) was 2.16 (95% CI 1.68–2.77; p < 0.001) (¹⁰).

Extended-release metoprolol succinate: achieved dose versus outcomes in MERIT-HF

Change in resting heart rate or EHR is generally considered an effective measure of the degree of β₁-blockade. However, the role of change in heart rate as a surrogate measure of clinical efficacy in heart failure has not been established. Further, the optimal β-blocker dose in heart failure has not been determined, as none of the prospective, definitive mortality trials were designed to address the issue of dose-response. An exploratory post hoc analysis of MERIT-HF evaluated the heart rate during uptitration and the dose of ER metoprolol succinate achieved vs clinical outcome. Two patient groups were defined: those who achieved an ER metoprolol succinate dose of ≤100 mg daily (low dose) and those who achieved >100 mg daily (high dose). The low-dose group was slightly older (65.9 vs 62.5 years), had somewhat more patients in New York Heart Association class III/IV (67 vs 53%), and had more patients with an ischemic cause of disease. Baseline blood pressure was somewhat lower in the low-dose subgroup. These characteristics suggest that the patients in the low-dose group were potentially at higher risk than those in the high-dose group. There was no difference in baseline heart rate between the low- and high-dose groups. At the end of titration, despite the difference in dose achieved, heart rate was the same in both groups (67 beats/min). This suggests a similar degree of β-blockade in both groups but an increased sensitivity to the β-blocker in the low-dose group. Both the low- and high-dose groups experienced a similar risk reduction in mortality and morbidity, a finding that is consistent with the similar degree of β-blockade in both groups (¹⁸).

Extended-release metoprolol succinate: cardioselectivity in heart failure

In MERIT-HF, the maximum target dose was 200 mg once daily (¹⁹). There has been concern that cardioselectivity may not be maintained at the target dose of 200 mg, particularly as β₁-receptors are selectively downregulated in heart failure, which results in a relative increase in β₂-receptors from 20–30% to 30–40% of the total (²⁰). Despite downregulation, however, β₁-receptors still predominate over the β₂-receptors and their activation has been shown to result in more severe pathogenic consequences (²¹). In addition, in prospective heart failure mortality trials, both β₁-selective and nonselective β-blockers have resulted in similar reductions in mortality and morbidity (^22,23). Thus, the decrease in β₁-receptor density seems to be of little relevance with respect to the clinical and remodeling effects of β-blockade.

Abrahamsson et al. (¹¹) demonstrated that the cardioselectivity of metoprolol is maintained up to a plasma concentration of approximately 300 n M; at concentrations above this, β₁-selectivity diminishes and blockade of β₂-receptors increases. Peak plasma concentrations produced by 200 mg ER metoprolol succinate and 50 mg metoprolol IR at steady state are similar, and below 300 n M, and therefore, it follows that the degree of cardioselectivity achieved during the peak plasma concentrations should also be similar (¹⁰). The cardioselectivity of metoprolol, as determined by the clinical marker of forced expiratory volume (FEV₁), was reported after investigators compared metoprolol IR, propranolol, and placebo in patients with asthma (²⁴). Although both active treatments demonstrated equipotent effects on β₁-receptors evidenced by similar decreases in heart rate, only propranolol demonstrated significant β₂-receptor activity evidenced by the near complete inhibition of isoprenaline effects on FEV₁ (Fig. 4) (²⁴). The effect of metoprolol 50 mg on FEV₁ was not different from that of placebo, indicating that this dose of metoprolol is β₁-selective. In a later study, other investigators compared the effects of single doses of ER metoprolol succinate 100 mg and 200 mg, atenolol 100 mg, and placebo in patients with asthma (²⁵). FEV₁ was significantly lower after treatment with atenolol compared with either dose of metoprolol (mean difference: −0.28 between atenolol 100 mg and ER metoprolol succinate 200 mg and −0.34 between atenolol 100 mg and ER metoprolol succinate 100 mg; p < 0.05) or placebo (mean difference: −0.41; p < 0.05); however, no significant difference in FEV₁ was found between placebo and either dose of ER metoprolol succinate. Furthermore, although the mean maximum plasma concentration of ER metoprolol succinate 200 mg (143 ± 99 n M) was more than double that of ER metoprolol succinate 100 mg (64 ± 47 n M), no significant difference was found between the FEV₁ produced by either regimen. There was no decrease in cardioselectivity with the 200-mg dose compared with the 100-mg dose (²⁵). Compared with atenolol 100 mg, ER metoprolol succinate 200 mg had less impact on β₂-receptor-mediated bronchodilation and thus was more cardioselective. These findings conflict with previous findings (²⁶) in which no difference was observed between metoprolol IR 100 mg and atenolol 100 mg in effects on FEV₁ (²⁵). It is suggested that ER metoprolol succinate may have enhanced cardioselectivity because of the lower, more consistent plasma concentrations characteristic of the ER formulation (^25,27). The greater selectivity of ER metoprolol succinate 100 mg compared with atenolol 100 mg has been confirmed in humans by comparing the extent to which each blocked the hypokalemic response to IV terbutaline (²⁸).

FIG. 4.: Mean increase over basal forced expiratory volume (FEV₁) in asthmatic patients during isoprenaline infusion after pretreatment with placebo, immediate-release (IR) metoprolol 50 mg, and propranolol 40 mg. Observe how the nonselective β-blocker propranolol almost completely inhibited the effect on FEV₁ for all doses of isoprenaline, whereas metoprolol IR 50 mg was not different from placebo. Reproduced with permission from Thiringer and Svedmyr (²⁴).

Tolerability

The cardioselective property of a β₁-selective blocker such as metoprolol has the potential for a more favorable tolerability profile. For example, bronchial constriction and disruption of glucose homeostasis associated with β₂-receptor stimulation may be of particular concern in patients with asthma or diabetes mellitus. The tolerability of ER metoprolol succinate was comparable to placebo in the MERIT-HF trial as assessed by all-cause discontinuations as well as discontinuations due to adverse events (^19,22). Results of MERIT-HF demonstrated that most patients were able to achieve the 200-mg target dose of ER metoprolol succinate. At the end of the study, the mean daily ER metoprolol succinate dose was 159 mg; 87% of patients received ≥100 mg, and 64% received the 200-mg target dose. Compared with the placebo group, ER metoprolol succinate was associated with 10% fewer discontinuations due to any cause and 25% fewer discontinuations due to worsening heart failure (^19,22). Adverse events such as pulmonary edema, bronchospasm, depression, impotence, hypoglycemia, or new-onset diabetes mellitus were similar on ER metoprolol succinate and placebo (28a). The mean heart rate at the end of the study was decreased by 14 beats/min, with no evidence of tolerance to ER metoprolol succinate. The favorable tolerability profile may result from a combination of β₁-receptor selectivity and fairly consistent plasma concentrations.

In a study conducted by Kukin et al. (²⁹), patients were randomly assigned to receive initial doses of metoprolol IR 6.25 mg or ER metoprolol succinate 25 mg and titrated over several weeks to a target dose of metoprolol IR 50 mg twice daily or ER metoprolol succinate 100 mg once daily. This study showed that despite the fourfold greaterstarting dose of ER metoprolol succinate, the acute and chronic effects on cardiac index, systemic vascular resistance, stroke volume index, stroke work index, resting heart rate, and pulmonary capillary wedge pressure were similar on ER metoprolol succinate and on metoprolol IR (Fig. 5). The investigators suggested that ER metoprolol succinate was more easily and rapidly uptitrated to the target dose than metoprolol IR in patients with heart failure (²⁹). These results, as well as those of the MERIT-HF trial, suggest that ER metoprolol succinate is safe and well tolerated and therefore may possess significant advantages over the IR formulation in the treatment of chronic heart failure.

FIG. 5.: Pulmonary capillary wedge pressure, stroke volume index, systemic vascular resistance, and stroke work index at baseline (B), peak 2 h after initial dose (P), long-term trough (LT-b) and 3 months of metoprolol therapy, and long-term peak (LT-p) 2 h after dose. Error bars are SEM. p values show differences between B and P, B and LT-b, and LT-b and LT-p within groups. Symbols under the lines refer to immediate-release (IR) metoprolol and those above the lines refer to extended-release (ER) metoprolol succinate. *p < 0.001; †p < 0.01; §p < 0.05. Reprinted with permission from American College of Cardiology (J Am Coll Cardiol 2000;35:45–50).

CONCLUSION

The ER metoprolol succinate provides a near constant rate of drug delivery for approximately 20 h, independent of food intake and gastrointestinal pH. Once-daily dosing of this ER formulation produces a consistent plasma level and consistent β₁-blockade over 24 h, in contrast to the marked peaks and troughs characteristic of IR metoprolol. Additionally, ER metoprolol succinate maintains cardioselectivity throughout the dosing interval—even after a 200-mg dose. ER metoprolol succinate is well tolerated in patients with heart failure and may offer advantages over metoprolol IR during initiation and uptitration. The favorable tolerability profile can be attributed to the unique formulation and pharmacokinetic properties of ER metoprolol succinate.