Sex-related differences in the pharmacokinetics of isosorbide-5-mononitrate (60 mg) after repeated oral administration of two different prolonged release formulations

To identify differences in the disposition of isosorbide-5-mononitrate between male and female volunteers.Plasma concentration and area under the concentration-time curve (AUC(SS)) data of isosorbide-5-mononitrate were obtained in a randomized, crossover, multiple-dose bioequivalence study in 24 subjects (12 females and 12 males). Participants received a single oral dose of 60 mg isosorbide-5-mononitrate prolonged-release tablet formulation (formulations I and II) on each of 6 consecutive days. Plasma isosorbide-5-mononitrate concentrations were determined according to validated methods involving liquid chromatography mass spectrometry.A total of 2 x 24 plasma concentration-time curves of the parent drug could be analyzed. The intersubject variation in plasma concentrations ranged from 25-50% (coefficient of variation). With both formulations, the mean plasma concentration-time curves for males and females ran parallel. The parameters Cmax, Cmin, AUC(SS), and AUC(SS)/kg in females were significantly higher than in males (p < 0.0001). This difference was solely attributed to the difference in body weight (p = 0.0024) and body mass index between males and females (p = 0.0113). Seven females showed a t = 0 = 24 h (Cmin) plasma concentration that was twice as high as the other 5 females and all the males; 125 +/- 12.2 ng/ml versus 59.3 +/- 9.2 ng/ml, respectively, in females (p < 0.0001) and 56.3 +/- 6.9 ng/ml in males (p < 0.0001). With both formulations, females in the n = 7 group had a longer t(1/2) and MRT than females in the n = 5 group, 5.06 +/- 0.76 h, 11.2 +/- 0.55 h versus 4.19 +/- 0.56, 9.40 +/- 0.62 h (p = 0.0057). The male group did not show this phenomenon, their disposition was similar to that of the female group of n = 5.The difference found in the Cmax and AUC(SS)/kg of isosorbide-5-mononitrate between male and female subjects must be due to the difference in dose/kg, following a standard dose of 60 mg. Fixed dose administration is common practice due to the available pharmaceutical formulations, while in the ideal situation the dose should be based on dose/kg or titrated to the required clinical effect.