Bioequivalence of fixed dose combination of atorvastatin 10 mg and aspirin 150 mg capsules: a randomized, open-label, single-dose, two-way crossover study in healthy human subjects.

The present study evaluated the bioavailability and bioequivalence of fixed dose combination test formulation (atorvastatin 10 mg and aspirin 150 mg capsule) against marketed reference formulations (Lipitor® tablets 10 mg and Nu-Seals tablets 75 mg). This study was an open label, balanced, randomized, 2-treatment, 2-period, 2-sequence, single dose, crossover trial in 80 healthy adult human volunteers under fasting conditions. Plasma concentrations of atorvastatin, aspirin and salicylic acid were quantified using LC-MS/MS method. Pharmacokinetic parameters were estimated by noncompartmental model and mean pharmacokinetic parameters were comparable between test and reference formulations. The mean pharmacokinetic parameters (AUC0-t, AUC0-∞, Cmax, Cmax /AUC0-t and Cmax/AUC0-∞) for atorvastatin test and reference formulations were (52.69 ng.h/mL, 55.64 ng.h/mL, 9.45 ng/mL, 0.18 1/h and 0.17 1/h) and (52.20 ng.h/mL, 55.38 ng.h/mL, 10.25 ng/mL, 0.20 1/h and 0.19 1/h) respectively; and for aspirin were (1 378.62 ng.h/mL, 1 383.90 ng.h/mL, 1 022.18 ng/mL, 0.75 1/h and 0.75 1/h) and (1 314.17 ng.h/mL, 1 314.50 ng.h/mL, 985.90 ng/mL, 0.75 1/h and 0.75 1/h) respectively. Where as for salicylic acid, above parameters were (42 357.57 ng.h/mL, 44 139.47 ng.h/mL, 9 820.15 ng/mL, 0.24 1/h and 0.23 1/h) and (40 217.08 ng.h/mL, 42 032.44 ng.h/mL, 9 569.18 ng/mL, 0.24 1/h and 0.24 1/h) respectively for test and reference formulations. The 90% confidence intervals of atorvastatin and salicylic acid for AUC0-t, AUC0-∞, Cmax, Cmax /AUC0-t and Cmax/AUC0-∞ parameters were found to be within the acceptable regulatory bioequivalence limits. In conclusion, the new fixed dose combination test formulation was bioequivalent to the reference formulations under fasting conditions.

Bioequivalence study of two subcutaneous formulations of dalteparin: randomized, single-dose, two-sequence, two-period, cross-over study in healthy volunteers.

OBJECTIVE: This study assessed relative bioavailability of a new subcutaneous formulation, test (T) (dalteparin sodium 95000 IU/3.8 mL) with the branded product (R) in healthy subjects to meet the regulatory requirements of bioequivalence in the US. METHODS: This was an open label, randomized, single dose, two-sequence, two-period cross-over study under fasting conditions. A total of 88 healthy adult volunteers were randomized to either of the treatment arms (T or R) separated by a washout period of 7 days. Pharmacodynamic surrogates, namely anti-Xa and anti-IIa activity, heparin clotting assay (heptest), and activated partial thromboplastin time (aPTT) were used as a tool to establish bioequivalence between these two formulations. Blood samples were collected up to 36 h post-dose to characterize the primary pharmacokinetic parameters A max, AUC0- t , and AUC0-∞ for anti-Xa and anti-IIa and heptest; parameters (Δt )max and AU(Δt ) for aPTT. RESULTS: For anti-Xa activity, the means (SD) of A max (IU/mL) were 1.34 (0.25) [range = 0.59-2.03] and 1.39 (0.35) [range = 0.65-2.69]; AUC0- t (IU•h/mL) values were 11.4 (2.76) [range = 2.89-19.5] and 12.1 (2.87) [range = 2.52-21.30]; AUC0 - ∞ (IU•h/mL) values were 13.1 (3.59) [range = 3.15-28.2] and 14.5 (4.97) [range = 2.79-36.1] for test and branded formulations, respectively. For anti-IIa activity, the means (SD) of A max (IU/mL) were 0.34 (0.12) [range = 0.14-0.72] and 0.34 (0.13) [range = 0.11-0.84]; AUC0- t (IU•h/mL) values were 2.05 (0.72) [range = 0.61-4.69] and 2.11 (0.76) [range = 0.84-4.80]; AUC0 - ∞ (IU•h/mL) values were 2.47 (0.80) [range = 0.76-6.29] and 2.61 (0.86) [range = 1.31-5.36], for test and branded formulations, respectively. The 90% CI for all the primary pharmacokinetic parameters of all the pharmacodynamic surrogates tested met the regulatory bioequivalence criterion of 80.00-125.00%. CONCLUSION: The test product met the US regulatory criteria of bioequivalence relative to the branded product in this single dose bioequivalence study. Study limitations include open-label single dose design.