Pharmacokinetic profile of a new controlled-release isosorbide-5-mononitrate 60 mg scored tablet (Monoket Multitab ®)

• Published in: European journal of pharmaceutics and biopharmaceutics 2002, Vol.53 (1), p.49-56
• Main Authors: Stockis, Armel, De Bruyn, Steven, Deroubaix, Xavier, Jeanbaptiste, Bernard, Lebacq, Edouard, Nollevaux, Fabrice, Poli, Gianluigi, Acerbi, Daniela
• Format: Article
• Language: English
• Subjects: Adult; Analysis of Variance; Angina pectoris; Antianginal agents. Coronary vasodilator agents; Biological and medical sciences; Cardiovascular system; Chemistry, Pharmaceutical; Cross-Over Studies; Delayed-Action Preparations - pharmacokinetics; Dietary Fats - metabolism; Drug Administration Schedule; Drug–food interaction; Fasting - blood; Food-Drug Interactions - physiology; General pharmacology; Humans; Isosorbide Dinitrate - administration & dosage; Isosorbide Dinitrate - analogs & derivatives; Isosorbide Dinitrate - blood; Isosorbide Dinitrate - pharmacokinetics; Isosorbide-5-mononitrate; Male; Medical sciences; Middle Aged; Pharmaceutical technology. Pharmaceutical industry; Pharmacokinetics; Pharmacology. Drug treatments; Sustained-release; Tablets; Vasodilator Agents - administration & dosage; Vasodilator Agents - blood; Vasodilator Agents - pharmacokinetics
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/S0939-6411(01)00210-7

The influences of food, tablet splitting, and fractional dosing on the pharmacokinetics of a new controlled-release double-scored tablet containing 60 mg isosorbide-5-mononitrate (Monoket Multitab ®) were investigated in healthy male volunteers. Food interaction was evaluated after single dose administration under fasted conditions and after a standard high-fat breakfast. The effect of tablet splitting was assessed at steady-state, after 5 days of once daily dosing with the tablet taken intact or trisected. The influence of fractional dosing was assessed after 1 and 6 days of daily regimen of 40 mg in the morning (2/3 of a tablet) and 20 mg in the evening (1/3 of a tablet). The pharmacokinetics of isosorbide-5-mononitrate after taking the tablet intact or in three fragments were very similar with a mere 10% increase of maximum plasma concentration ( C max) for the latter, while the time to peak ( T max) decreased from 5 to 4 h and areas under the concentration vs. time curves (AUCs) were virtually unchanged. Morning trough concentration reached 53 and 46 ng/ml, respectively. Administration of the intact tablet after a high-fat breakfast increased C max by 18% and AUC by 21%, and slightly delayed T max from 5 to 6 h. During fractional dosing, morning and evening C max reached 364 and 315 ng/ml on the first day, and 373 and 300 ng/ml on the 6th day, respectively. The ratio of AUC 0–24 h on the last day to AUC∞ on the first day, was 82.1% (confidence limits 71.7–94.1%) possibly resulting from peripheral volume expansion. The release characteristics of Monoket Multitab ® are thus moderately influenced by concomitant intake of food and to a very minor extent by tablet breaking. Fractional dosing allows to achieve lower peak and higher morning trough levels, while total exposure is comparable to that during once daily dosing (AUC 0–24 h, s.s. of 5.55±1.78 and 5.71±1.08 μg h/ml).