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,) AUC(0–)(t), and AUC(0–∞) 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]; AUC(0–)(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]; AUC(0)(–)(∞) (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]; AUC(0–)(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]; AUC(0)(–)(∞) (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.