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

OBJECTIVE: To identify differences in the disposition of isosorbide-5-mononitrate between male and female volunteers. METHOD: 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. RESULTS: 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. CONCLUSION: 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.

Bioavailability of ambroxol sustained release preparations. Part II: Single and multiple oral dose studies in man.

The bioavailability of a new ambroxol sustained release preparation (75 mg) based on a dialyzing membrane for controlled release was studied in healthy volunteers after single and multiple oral dose in comparison with a standard sustained release formulation in a cross-over study under carefully controlled conditions. Plasma concentrations of ambroxol were measured by means of a HPLC method. Based on AUC data both preparations are found to be bioequivalent, but show different plasma concentration profiles. The test preparation showed a more pronounced sustained release profile than the reference preparation (single dose) resulting in significantly higher steady state plasma levels.

Bioavailability of ambroxol sustained release preparations. Part I: In vitro dissolution studies.

The in vitro dissolution of two ambroxol-HCl containing sustained release preparations (75 mg) and the effect of pH of the dissolution medium on the dissolution rats were investigated. The studies were carried out using the USP XXI paddle method. A new ambroxol HCl sustained release formulation based on a dialyzing membrane for controlled release shows a longer release action as compared to a standard sustained release preparation from commercial source which is based on spheroids constituted by a lipid matrix. The in vitro release rate of the latter product also appears to be more pH dependent.