A pilot double-blind randomized placebo-controlled study of molsidomine 16 mg once-a-day in patients suffering from stable angina pectoris: correlation between efficacy and over time plasma concentrations.
OBJECTIVE
A new once-a-day (o.a.d.) formulation of molsidomine (16 mg) was evaluated in patients with stable angina pectoris. The aims were to characterize its pharmacokinetics after a single dose, to demonstrate its clinical efficacy and safety versus placebo and to investigate correlations between pharmacokinetics and pharmacodynamics.


METHODS
Forty-two patients were recruited in a double-blind, crossover, randomized placebo-controlled trial. The pharmacokinetics of molsidomine and SIN-1, its active metabolite, were determined at specific time points (3, 6, 10, 14, 18, 22 and 24 h) after the administration of a single dose of molsidomine 16 mg o.a.d. in all patients distributed into seven groups. Twenty-eight of these 42 patients showed a positive baseline cycloergometric exercise test response during the run-in placebo period and were used to compare the efficacy of molsidomine to placebo. Relationships between plasma concentration in molsidomine or SIN-1 and ischemic threshold were assessed in 16 of the 28 patients with a positive exercise test at baseline. Indeed, the censored variable ischemia-limited tolerance to exercise could not be evaluated in those patients who did not show exercise-induced ischemia anymore under molsidomine 16 mg o.a.d. Pharmacokinetic-pharmacodynamic relationships were evaluated using regression models and correlation coefficients.


RESULTS
The highest average concentration in molsidomine and SIN-1 occurred after 6 h, then a plateau of 15-20 ng/ml molsidomine and 0.8-3.0 ng/ml SIN-1 was maintained for at least 8 h and the mean residual molsidomine concentration 24 h post-drug intake was around 8 ng/ml, still in the effective range of 5-10 ng/ml. A significant increase in total workload (+52 W min, P=0.009), total exercise time (+32 s, P=0.003) and time to angina (+25 s, P=0.016) was measured with molsidomine 16 mg o.a.d. relative to placebo. Using linear regression, significant correlation coefficients were determined between molsidomine plasma concentrations (but not SIN-1) and exercise test improvements (r=0.827, P<0.001 for the total workload; r=0.772, P<0.001 for the total exercise time; and r=0.566, P=0.028 for the time to 1 mm ST-segment depression).


CONCLUSIONS
The pharmacokinetics of molsidomine 16 mg in patients with stable angina pectoris is compatible with a o.a.d. dosage regimen. This o.a.d. formulation is effective and well-tolerated, providing a 24-h therapeutic control of myocardial ischemia. A positive and significant linear relationship between molsidomine plasma concentration and the increase in exercise tolerance was observed.
Therabel Pharma S.A., Rue Van Ophem 108, 1180 Brussels, Belgium. infos@research.therabel.com
Roger
R
Messin
Tamas
T
Fenyvesi
Fabienne
F
Carreer-Bruhwyler
Jacques
J
Crommen
Patrice
P
Chiap
Philippe
P
Hubert
Claude
C
Dubois
Jean-Pierre
JP
Famaey
Joseph
J
Géczy
D000368:Aged; D000787:Angina Pectoris / Q000188:drug therapy* / Q000503:physiopathology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005080:Exercise Test; D017079:Exercise Tolerance; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008981:Molsidomine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020030:Nitric Oxide Donors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010865:Pilot Projects
D020030:Nitric Oxide Donors; D008981:Molsidomine