A new isosorbide dinitrate extended-release formulation: pharmacokinetic and clinical parameters in patients with...

In a double-blind, cross-over study the acute clinical efficacy and pharmacokinetic profile of a newly developed isosorbide dinitrate extended-release (ISDN-ER) formulation (10 mg immediate release and 60 mg slow release) were examined in eight angina patients. Exercise tests were done 1 h before and 1, 6 and 10 h after acute ISDN or placebo; similar testing was repeated after 14 days of open-labelled treatment. At 1, 6 and 10 h after administration, ISDN-ER significantly reduced the mean ST depression at highest comparable workload (HCWL) by 0.8, 0.6, and 0.6 mm, respectively. Total exercise duration increased significantly by 46, 42 and 72 s. The rate-pressure product at HCWL was not reduced significantly at any time, while digital plethysmography demonstrated a significant effect on arterial pulse curves throughout the 10 h. After 14 days of once-daily treatment, similar or somewhat attenuated clinical effects were observed. Pharmacokinetic measurements showed a first peak of ISDN at 1-2 h and a second peak at 4-5 h. The 5-isosorbide mononitrate (5-ISMN) metabolite peaked at 5-8 h and remained high at 10 h. After 14 days of treatment, the mean plasma concentrations of ISDN and 5-ISMN before drug were 0 and 69 ng.ml-1, respectively. Thus, satisfactory acute clinical efficacy and low nitrate levels during the night were observed. However, long-term clinical efficacy needs to be established in larger, placebo-controlled trials.