Antihypertensive Properties of the Novel Calcium Antagonist Mibefradil (Ro 40-5967)
A New Generation of Calcium Antagonists?
Abstract Preclinical and initial clinical studies suggest that the novel calcium antagonist mibefradil has a unique combination of properties. Mibefradil was evaluated in a multicenter, double-blind, placebo-controlled, parallel group trial. After 4 weeks of a placebo run-in period, 202 eligible patients with mild to moderate hypertension were randomized to receive doses of 25, 50, 100, or 150 mg mibefradil or placebo once a day for 4 weeks. Blood pressure and heart rate were measured repeatedly at trough and peak (24 and 2 to 6 hours postdose, respectively) at the end of each period. Concentration-effect relationships were evaluated at trough on the last treatment day. A significant (P<.01 versus placebo) drop in blood pressure (diastolic and systolic) was observed at trough and peak in all mibefradil groups, with a trough-peak ratio greater than 0.8, high response rate, and a significant dose-response relationship (P<.001). The full antihypertensive effect of mibefradil was achieved within 1 to 2 weeks and was associated with a slight dose-dependent decrease in heart rate and increase in PQ time. Clear dissociation was observed between the effect on blood pressure and PQ time when concentration-effect relationships were evaluated. These results indicate that mibefradil is an effective and well-tolerated antihypertensive compound at doses of 25, 50, and 100 mg once daily. The incidence of treatment-related adverse events observed in the 25-, 50-, and 100-mg dose groups was lower than in the placebo group, but it was slightly higher in the 150-mg dose group, and three patients from this group were prematurely withdrawn because of an adverse event.
Calcium antagonists (CAs) have become an established treatment for hypertension and chronic stable angina pectoris over recent years.1 2 Despite markedly different chemical structures, all compounds of the three main classes of CAs (dihydropyridines, phenylalkylamines, and benzothiazepines) inhibit the inward current of calcium ions through the slow (L-type) calcium channels.3 4 However, because of binding at different receptor sites, different pharmacokinetic properties, and different effects at the levels of the cardiovascular (coronary and peripheral arteries, cardiac conduction system, and myocardium) and extracardiovascular systems, each of these compounds has its own advantages and disadvantages.5 6 Although many new CAs are being developed, it is still not clear whether these new compounds will result in clinically important improvements in efficacy and tolerability.
Mibefradil (Ro 40-5967) is a novel CA from the new chemical structural class of benzimidazolyl-substituted tetraline derivatives.7 Mibefradil differs at the molecular level from existing CAs in two ways. First, it blocks L- and T-type calcium channels, with a more selective blockade of T-type channels, whereas other CAs block only the L-type channels.8 Second, mibefradil binds to a unique receptor site that probably overlaps the verapamil and SR3557 sites and can competitively displace the two compounds. Furthermore, through binding to the new site, mibefradil interferes allosterically with the diltiazem site without affecting dihydropyridine binding.9
The main mechanism of action of mibefradil is arterial vasodilation (coronary and peripheral) achieved through a direct effect on vascular smooth muscle,10 an effect shown to be associated with a slight decrease in HR.9 11 12 13 In contrast to verapamil and diltiazem, at equipotent doses, mibefradil was found to have no relevant depressant effect on myocardial contractility in several preclinical models.14 15 Similarly, initial clinical studies in patients with hypertension,11 patients with angina pectoris,12 and patients with impaired cardiac function (ejection fraction <40%) secondary to chronic ischemic heart disease13 confirmed the preclinical observation that treatment with mibefradil was not associated with negative inotropic effects. Instead, treatment with mibefradil improved cardiac function and slightly decreased HR.
Mibefradil has been shown to have a high bioavailability (about 90%) and a long half-life (17 to 25 hours), making it suitable for once-a-day treatment. Steady-state plasma levels are reached after 3 to 4 days. It is mainly eliminated by the biliary system.10 16
The unique molecular biology and favorable pharmacokinetic features of mibefradil as well as its ability to lower HR without negative intropic effect raise the expectation that mibefradil may have clinical benefits not associated with the traditional CAs.
We designed the present study of mibefradil to achieve the following objectives: (1) to evaluate the dose-response relationship of mibefradil and to establish the effective antihypertensive dose range; (2) to evaluate the duration of action of mibefradil by determining the peak and trough effects and trough-peak ratio; (3) to evaluate the kinetic-dynamic (concentration-effect) relationship of mibefradil by determining drug levels in plasma and changes in dynamic parameters (eg, BP, HR, and PQ interval); and (4) to evaluate the safety and tolerability of different mibefradil doses.
Study Design and Patient Selection
This was a multicenter, randomized, placebo-controlled, double-blind, parallel design, dose-finding trial in which the effect of four different mibefradil doses (25, 50, 100, and 150 mg) administered once daily for 4 weeks was evaluated compared with placebo in patients with mild to moderate essential hypertension.
Male and female outpatients, aged 18 to 70 years, with mild to moderate essential hypertension were screened after they provided written informed consent; if eligible, they were asked to discontinue all current antihypertensive medications. After 4 weeks of the single-blind placebo run-in period, patients were considered eligible for entry into the double-blind period if at the end of the third and fourth weeks of the run-in period their predose (24±2 hours after the last dose) SDBP was between 100 and 114 mm Hg and if their compliance was at least 80% (tablet counting). Those who qualified were given an additional placebo dose and asked to stay in the clinic for repeated BP measurements for 6 hours. Patients were randomized to one of the five groups of the active treatment period if the mean SDBP during the 2 to 6 hours after placebo (peak effect) was between 95 and 114 mm Hg.
During the 4 weeks of the active treatment period, patients were seen in the clinic for BP measurements at trough (predrug intake but 24±2 hours after the last dose) at the end of the first, second, and fourth weeks. On the last visit, patients were asked to stay in the clinic for repeated BP measurements for 6 hours.
Patients were excluded from the trial if they had severe, malignant, or secondary hypertension as well as any significant cardiac, renal, hepatic, neurological, hematologic, gastrointestinal, psychiatric, metabolic, or endocrinologic (except for diabetes mellitus and well-controlled hypothyroidism) disease. Patients with a body weight of more than 150% of ideal body weight and those with a history of alcohol or drug abuse were also excluded.
The study was performed in 10 centers of six European countries (Germany, the Netherlands, Sweden, Finland, Austria, and Denmark). It was approved by the local ethics committees and conducted according to the principles of the Declaration of Helsinki as amended in Tokyo, Venice, and Hong Kong.
BP was measured in duplicate with a calibrated mercury sphygmomanometer. Korotkoff phase I and V sounds were used for determination of systolic and diastolic BPs, respectively. Measurements were done in the same arm, appropriately supported at heart level, and by the same person after patients had rested at least 5 minutes in the sitting position. Standing BP was measured after 1 minute of standing, and HR was measured by pulse counting during the sitting and standing positions.
Blood for pharmacokinetic evaluation was drawn on the last day of active treatment at trough (24±2 hours after the last dose).
Physical examination was performed at the beginning and end of the study period, and body weight was measured on every visit. A regular 12-lead electrocardiogram was recorded during screening, at the fourth week of the run-in period, and on every visit during the active treatment period. Both QT and QTc were evaluated. Laboratory determinations, consisting of routine hematology, clinical chemistry, and urinalysis tests, were performed at the end of the placebo run-in period and after 1 and 4 weeks of active treatment. AEs, defined as any adverse changes from the patient’s baseline condition, including intercurrent illnesses, were recorded throughout the study and evaluated by the investigators for their severity (mild, moderate, or severe) and relationship to drug treatment (remote, probable, possible, or unrelated).
The analysis of the ITT population was regarded as the main analysis, whereas the standard analysis (protocol correct) provided supportive evidence of efficacy and allowed the assessment of the effect of premature withdrawals and protocol violations on the ITT analysis. The primary efficacy parameter was the change from baseline to week 4 in SDBP at trough. The secondary efficacy parameters were the change from baseline to week 4 in SSBP at trough, the change from baseline to week 4 in SDBP at peak, and response rates. In the ITT analysis, the last postbaseline measurement was carried forward to week 4 of active treatment if the patient did not complete the trial. Major protocol violators and patients who did not complete the active treatment period (premature withdrawal) were excluded from the standard analysis.
A subset analysis according to age, sex, and baseline SDBP was planned to be done descriptively because of the expected low number of patients per subgroup.
Dose-response relationship was evaluated by the linear trend test, applying the appropriate linear hypothesis in the ANOVA with treatment effect, center effect, and treatment-by-center interaction. Individual dose effect was evaluated by a pairwise comparison of each dose group with placebo using the appropriate contrast in the linear model mentioned above. A closed test was applied to ensure that the nominal significance level was kept at .05.
Of 315 hypertensive patients who were screened for study eligibility, 247 entered the placebo run-in period. During this period, 45 patients either failed to qualify for randomization or discontinued treatment for administrative reasons and were dropped. A total of 202 patients were randomly assigned to one of the five treatment groups, all of which were included in the ITT and safety analyses. Five patients were classified as major protocol violators and 3 did not complete the active treatment period because of AEs. Of the 202 randomized patients, 160 received mibefradil in one of the four doses, and the other 42 patients received placebo. The baseline characteristics of the patient population are summarized in Table 1⇓. The groups were well balanced with regard to their demographic parameters and SDBPs.
Only minor differences in BP were found between the ITT and standard analyses. Therefore, only the analysis of the ITT population is presented.
A highly significant linear dose trend (P<.001) in the decrease in SDBP at trough and peak after 4 weeks of active treatment was observed across the five groups treated with mibefradil (Table 2⇓, Fig 1⇓). A clinically relevant and statistically significant drop in SDBP was observed in all mibefradil groups when compared with placebo at both peak and trough. The trough-peak ratio was above 80% at all dose levels. This indicated that most of the effect achieved at peak was still present at trough. Changes over time in SDBP indicated that most of the antihypertensive effect was reached within the first week of active treatment (Fig 2⇓). The response rates according to different criteria with each dose level are summarized in Table 3⇓.
The decrease of SDBP was further descriptively analyzed by dividing the patients according to age (<60 versus ≥60 years old), sex (men versus women), and SDBP level at baseline (<105 versus ≥105 mm Hg; mild versus moderate). Treatment with the higher doses of mibefradil (100 and 150 mg) was associated with a slightly larger response in the older patients and in patients with a moderate increase in SDBP (Table 4⇓). A larger response was also observed in women compared with men at each dose level (Table 4⇓).
Changes in SSBP (linear trend test, decrease in SSBP at peak and trough, trough-peak ratio, and the time course of response during active treatment) and the statistical significance followed a pattern similar to SDBP in all treatment groups (Fig 1⇑).
There was a dose-dependent reduction from baseline in sitting HR at trough and peak after 4 weeks of active treatment in the ITT population (Fig 3⇓) with a statistically significant linear trend test (P<.01). The maximal reduction of −10.0 bpm was noted with the 150-mg dose. A clear correlation was observed between the baseline HR and magnitude of HR reduction (P<.001). In other words, the lower the HR at baseline, the smaller the HR decrease. The dose-dependent reduction in sitting HR at peak was of a lower magnitude than that recorded at trough (Fig 3⇓). The maximal reduction of −6.6 bpm was observed with the 100-mg dose.
Concentration-effect relationships with respect to potency and sensitivity were investigated for SDBP, SSBP, PQ interval, and HR. For all effects, the changes from baseline observed at the end of the 4-week treatment period were used. A hierarchy of models was tested and fitted to the data: stepwise response, step-linear response, Emax model, and sigmoidal Emax model. From a previous study it was known that at a steady state the observed effects (reduction in BP) could be related directly to the measured plasma concentrations as the hysteresis loop, present after a single dose treatment, has collapsed.17 The most appropriate model for BP and HR measurements was the Emax model. For PQ time, the linear model fitted the observations best.
For all effects investigated, a clear correlation between plasma concentration of unchanged mibefradil and observed effect could be established. There was a clear dissociation between the effects on BP and PQ time (Fig 4⇓) up to the highest plasma concentrations obtained with the 150-mg mibefradil dose. Thus, although the gain in effect (decrease in SDBP) achieved with the 150-mg dose compared with the 100-mg dose was relatively small, indicating that the effect was flattening, the respective increase in PQ time continued to rise in a dose dependent manner. When concentration-effect relationships were evaluated in men and women, no differences could be found. However, plasma concentrations in women were consistently higher than in men for each dose level.
Mean plasma concentrations at trough after chronic dosing for 4 weeks were proportional to the mibefradil dose (87±132, 230±91, 438±177, and 663±376 ng/mL, respectively).
Tolerability and Safety
When all AEs and treatment-related AEs were considered, fewer patients in the mibefradil groups had one or more events compared with the placebo group (35% versus 40% for all events and 18% versus 26% for treatment-related events, respectively) (Table 5⇓).
The most frequent AEs observed in this trial were leg edema, headache, and flushing. Although the overall incidence of leg edema in mibefradil patients was not different from the incidence observed in the placebo group, its frequency was dose related; only the 150-mg dose group reached levels higher than the placebo group. Headache was more frequently reported in the placebo-treated patients. Flushing was slightly more frequent in the mibefradil patients and was not dose related.
When treatment-emergent electrocardiographic changes were considered (Table 6⇓), the main findings observed in the mibefradil groups compared with the placebo group were dose-related first-degree AV block (PQ >200 milliseconds) and asymptomatic sinus bradycardia (a decrease of HR <55 bpm and a change from baseline >10 bpm). One case of nodal rhythm was observed in a patient treated with the 150-mg mibefradil dose. PQ interval increased in a dose dependent manner at both peak and trough, reaching 21.3±2.8 and 13.9±2.7 milliseconds, respectively, with the 150-mg dose.
Treatment-related AEs that resulted in discontinuation of therapy were reported in 1.9% (3/160) of the patients taking mibefradil. The reasons for discontinuation of treatment were asymptomatic sinus bradycardia, sinus bradycardia with chest discomfort, and transient collapse, all occurring in the 150-mg group. One patient in the 25-mg group was discontinued prematurely because of treatment failure defined as an increase in SDBP greater than or equal to 115 mm Hg on two consecutive visits.
Laboratory tests remained stable, and none of the observed individual changes could be related to mibefradil treatment.
The results of the present study clearly indicate that mibefradil is an effective once-a-day antihypertensive compound. The decrease in BP (systolic and diastolic) observed with all four doses of the compound at peak and trough was clinically relevant and statistically significantly greater than the effect observed in the placebo group. The highly significant linear-dose trend observed across the five treatment groups (peak and trough BPs) indicates that the increase in mibefradil dose is associated with an improvement in the magnitude of decrease and control of BP in hypertensive patients.
The high trough-peak ratio (>80%) observed at all dose levels indicates that BP control was sustained for the full 24-hour period devoid of wide trough-to-peak variation, an important aspect of safety for an antihypertensive drug; most of the antihypertensive effect was achieved gradually within 1 week of active treatment. These observations correlate well with the pharmacokinetic profile of mibefradil.10 18
On the basis of a descriptive analysis, a larger decrease in SDBP in older patients (<60 versus ≥60 years) and in patients with a moderate rather than mild increase in BP was observed only with the higher mibefradil doses (100 and 150 mg). When the effect of mibefradil on SDBP was evaluated in men and women, it seemed that the decrease in SDBP was larger in women at each dose level. However, this was not confirmed when concentration-effect relationships were evaluated. Thus, for the same plasma concentration of mibefradil, the decrease in SDBP in both sexes was similar. The differences between the response of men and women could be related to higher plasma concentrations observed in women at each dose level. This in turn could be because of the lower weight of women (68±17 versus 83±20 kg) or better compliance. Additional trials are needed to evaluate this observation further.
The antihypertensive effects observed with the four mibefradil doses in this trial suggest that the lowest and highest effective doses were not identified. However, population-kinetics or the concentration-effect relationship is a helpful tool for substantiating the dose-response relationship, especially if there is a tight relationship between drug effect and plasma concentration. Indeed, in a previous trial11 in which repeated measurements of the plasma concentration of mibefradil and BP were evaluated at both peak and trough at steady state, the observed effect could be directly related to the measured plasma concentration. In the present study, the further decrease in SDBP observed with the 150-mg dose was small compared with that observed with the 100-mg dose, indicating that the concentration-effect relationship was flattening. Moreover, in the shorter and smaller previous study (8 days of active treatment, 12 patients per group), in which the antihypertensive effects of 50, 100, 150, and 200 mg mibefradil were evaluated, no differences were seen between the effects of the 150- and 200-mg doses, and only a slight further decrease in SDBP was observed with the 150-mg dose compared with the effect of the 100-mg dose.11
The decrease in BP observed with the 25-mg mibefradil dose was significantly better than that seen with placebo, indicating that lower doses might still be effective. However, on the basis of the results of the concentration-effect relationship and the pharmacokinetic properties of mibefradil, it is predicted that lower doses of the compound might not be effective in lowering BP. This assumption is being evaluated further in other studies with lower doses of mibefradil.
The decrease in BP was associated with a dose-dependent decrease in HR at both peak and trough. However, the magnitude of HR reduction was directly related to the pretreatment (baseline) HR; the lower the HR at baseline, the lower the decrease in HR during active treatment with mibefradil. Thus, a low HR might not be a reason for avoiding treatment with mibefradil. The mechanism of the decrease in HR induced by mibefradil is not fully understood; however, the most likely explanation is a direct effect of the compound on the sinus node. This effect was shown in specific experiments in which mibefradil produced a dose-dependent decrease in sinus rate in an isolated sinoatrial preparation19 and in isolated perfused hearts.15 Increased vagal tone was not confirmed as a possible mechanism for the decrease in HR,20 and this observation could not be related to an antiadrenergic effect because no interaction with adrenergic receptors (α1, α2, and β) was observed in in vitro receptor binding experiments (Clozel JP, 1995, unpublished data). Moreover, when 50 and 100 mg mibefradil was added to the treatment regimens of hypertensive patients treated chronically with high doses of atenolol (100 mg/d), a further decrease in HR by a mean of 5 and 10 bpm, respectively, was observed.21 It might be expected that the effect of mibefradil on the sinus node would be offset by a reflex increase in adrenergic tone secondary to peripheral vasodilation. However, the results indicate that the action of mibefradil on the sinus node is the dominant effect overriding possible adrenergic stimulation, an effect that is also observed with verapamil and diltiazem.
Mibefradil was very well tolerated in the present study. Thus, fewer patients treated with mibefradil had one or more AEs compared with the placebo-treated patients. When each treatment group was evaluated separately, only patients treated with 150 mg mibefradil had slightly more AEs than the placebo group. The only dose-related AE observed in the mibefradil groups was leg edema, mainly seen in the 150-mg group. Although headache was more frequently reported in placebo-treated patients, the frequency of flushing reported in the mibefradil-treated patients was slightly higher than in the placebo group. In three patients in the 150-mg group, mibefradil treatment was prematurely discontinued because of AEs (asymptomatic sinus bradycardia, sinus bradycardia associated with chest discomfort, and transient collapse).
The main dose-related treatment-emergent electrocardiographic changes observed in the mibefradil groups in this trial were first-degree AV block and asymptomatic sinus bradycardia. However, the clear dissociation between the effect on BP and PQ time observed with plasma concentrations of mibefradil obtained with doses up to 100 mg indicates that BP control could be achieved with a relatively small increase in PQ interval.
The decrease in HR associated with mibefradil treatment is clinically advantageous because hypertensive patients have or might develop ischemic heart disease; a lower HR results in a reduction in cardiac workload and oxygen need. Moreover, recent epidemiological studies indicate that lower HR might be associated with a better prognosis with regard to cardiovascular morbidity and mortality.22 23 24 25 26
Although the risk-benefit ratio of the 25-, 50-, and 100-mg doses of mibefradil is excellent, the efficacy gain with the 150-mg dose is relatively small compared with the increase in the number and kind of AEs. Therefore, the highest recommended dose of mibefradil might be 100 mg. Of course, pending the publication of large controlled clinical trials, caution must be exercised in drawing conclusions about the safety and tolerability of mibefradil.
In summary, mibefradil, the first of a new structural class of CAs, is an effective once-a-day antihypertensive compound. Treatment with mibefradil was associated with smooth control of BP over the 24-hour period, and its full antihypertensive effect was achieved within 1 to 2 weeks after active treatment was started. The reduction in BP resulted in a high response and was associated with a dose-dependent decrease in HR. These properties, combined with the tight concentration-effect relationship, the unique binding properties at the level of the calcium channels, and the lack of a negative inotropic effect shown in the preclinical and clinical studies, suggest that mibefradil has a unique pharmacological profile that might distinguish it from other CAs.
Selected Abbreviations and Acronyms
|bpm||=||beats per minute|
|Emax||=||maximal effect due to drug action|
|SDBP||=||sitting diastolic blood pressure|
|SSBP||=||sitting systolic blood pressure|
This study was supported by F. Hoffmann–La Roche Ltd, Basel, Switzerland. The following are the members of the Mibefradil International Study Group: Dr Per-Olof Andersson, Medicinska Kliniken, Höglandssjukhuset, Eksjö, Sweden; Dr Ib Fraemohs, Allingaabro, Denmark; Dr Martin Harsch, F. Hoffmann–La Roche Ltd; Dr Timo Honkanen, Helsinki, Finland; Jirina Kupsky-Prochazka, F. Hoffman–La Roche Ltd; Dr Norbert Neumann, F. Hoffmann–La Roche Ltd; Dr Tore Schjönberg, Städhälsan, Stockholm, Sweden; Dr Christine Spiegler, F. Hoffmann–La Roche Ltd; Dr Peter-Lars Stahnke, Hamburg, Germany; Daniela Welford, F. Hoffmann–La Roche Ltd; Dr Horst Welker, F. Hoffmann–La Roche Ltd; and Dr Alexander Windsor-Topolsky, Ambulatorium Mariahilf, Vienna, Austria.
Reprint requests to Dr Peter J.L.M. Bernink, Martini Ziekenhuis, v Ketwich Verschuurlaan 82, 9721 5W Groningen, Netherlands.
- Received July 12, 1995.
- Revision received August 21, 1995.
- Accepted November 20, 1995.
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