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

Abstract

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.

Keywords: Bioavailability; Bioequivalence; Dalteparin; Subcutaneous.

Figure 1.

(A) anti-Xa activity and (B) anti-IIa activity vs time curve after single dose administration of test and branded product of dalteparin sodium.

Figure 2.

(A) heptest and (B) aPTT activity vs time curve after single dose administration of test and branded product of dalteparin sodium.