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.