Clinical Pharmacokinetics of Once-Daily Molsidomine

Abstract

Molsidomine is a direct nitric oxide donor routinely used in the oral treatment of stable angina pectoris. It was initially available as 4mg immediate-release tablets to be taken three to four times a day. New galenic formulations have been developed: prolonged-release molsidomine 8mg to be administered twice daily and, more recently, prolonged-release molsidomine 16mg to be taken once daily, the latter being based on the patented and US FDA-approved Geomatrix® technology. This study has four objectives: (i) to compare and differentiate the pharmacokinetics of the different molsidomine formulations after single- and repeated-dose administrations; (ii) to put the new formulations in perspective with the literature and the critical minimal efficacy plasma molsidomine concentration of 5 µg/L; (iii) to demonstrate a possible bioequivalence between 8mg twice-daily and 16mg once-daily tablets when used at their recommended therapeutic dosage regimen; and (iv) to assess the effect of food and age on the absorption, distribution, and elimination of the new once-daily formulation. Different dosages of various formulations of molsidomine were administered to young and elderly healthy volunteers and plasma concentrations of molsidomine and its active metabolite, linsidomine (SIN-1), were determined. Plasma concentrations were determined using solid-phase extraction and enrichment of the extracts on a short column followed by elution of the analytes by liquid Chromatographic mobile phase and ultraviolet detection. Compared with previous formulations, molsidomine 16mg once daily showed an increased time to maximum plasma concentration and a tendency to a lower mean maximum plasma concentration. Plasma molsidomine concentrations were always above the efficacy threshold of 5 µg/L during the whole 24-hour cycle and the concentration at trough was still in the therapeutic range. No drug accumulation was observed after repeated administration. Bioequivalence between molsidomine 16mg once daily and molsidomine 8mg twice daily could not be demonstrated after 1 and 5 days of treatment, the relative bioavailability being significantly larger with the latter regimen. Pharmacokinetics of molsidomine 16mg once daily was not significantly affected by either concomitant food ingestion (no major effect of a high-fat meal) or aging (no major difference between young and elderly healthy volunteers). Molsidomine 16mg once daily allowed the maintenance of a therapeutically active plasma concentration over 24 hours after single or repeated oral administration. The bioavailability of molsidomine from the once-daily preparation is apparently not affected by concomitant administration of food or age of the recipient.