Bioequipotency of idraparinux and idrabiotaparinux after once weekly dosing in healthy volunteers and patients treated for acute deep vein thrombosis

Abstract

Aim: To assess the bioequipotency of equimolar doses of idraparinux (2.5 mg) and idrabiotaparinux (3.0 mg).

Method: In a phase I study, 48 healthy male volunteers were randomized to a single subcutaneous injection of idrabiotaparinux or idraparinux, followed by plasma sampling over 27 days. In a prospective substudy of the phase III EQUINOX trial, 228 patients treated for acute symptomatic deep vein thrombosis received idrabiotaparinux or idraparinux once weekly for 6 months. Plasma sampling was performed within 5 days following the last injection. The primary pharmacodynamic endpoint was the inhibition of activated factor X (FXa) activity. Maximal anti-FXa activity (Amax) and area under anti-FXa activity vs. time curve (AAUC) were calculated. Safety and tolerability were also assessed.

Results: In both studies, pharmacodynamic anti-FXa vs. time profiles of idrabiotaparinux and idraparinux were superimposable. Ratio estimates (90% confidence intervals [CIs]) for idrabiotaparinux : idraparinux were 0.96 (0.89, 1.04) for Amax and 0.95 (0.87, 1.04) for AAUC in the phase I study, and 1.11 (1.00, 1.22) for Amax and 1.06 (0.96, 1.16) for AAUC at month 6 in the EQUINOX substudy. Idrabiotaparinux and idraparinux were considered bioequipotent because 90% CIs were within the pre-specified interval (0.80, 1.25). Study treatments were well tolerated.

Conclusion: Pharmacodynamic parameters reported after single dose in healthy volunteers and after repeated once weekly dosing in patients demonstrated the bioequipotency of idrabiotaparinux and idraparinux based on FXa inhibition. These outcomes support the use of an idrabiotaparinux dose bioequipotent to an idraparinux dose in large clinical trials, and the possibility to substitute idrabiotaparinux to idraparinux for the treatment of venous thromboembolism.

Trial registration: ClinicalTrials.gov NCT00311090.

© 2012 Sanofi R&D. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Figures

Figure 1

Chemical structures of idraparinux and idrabiotaparinux

Figure 2

Study design schema of the EQUINOX trial and substudies. DVT, deep vein thrombosis

Figure 3

Mean pharmacodynamic anti-factor Xa activity vs. time profiles of idrabiotaparinux (3.0 mg) and idraparinux (2.5 mg) after single subcutaneous equimolar dosing in healthy volunteers (n = 24 per treatment group). LLOQ, lower limit of quantification. , idrablotaparinux; , idraparinux

Figure 4

Pharmacodynamic anti-factor Xa activity vs. time profiles of idrabiotaparinux (3.0 mg) and its debiotinylated metabolite (SSR115771) vs. idraparinux (2.5 mg) after repeated subcutaneous equimolar dosing in patients with deep vein thrombosis in the EQUINOX bioequipotency substudy at month 6 (n = 114 per treatment group). , idrabiotaparinux and debiotinylated metabolite, mean predictions; , idraparinux, mean predictions; , idrabiotaparinux and debiotinylated metabolite, mean observed data; , idraparinux, mean observed data

Figure 5

Pharmacodynamic anti-factor Xa activity vs. time profiles of idrabiotaparinux (3.0 mg) vs. idraparinux (2.5 mg) after repeated subcutaneous equimolar dosing in patients with deep vein thrombosis over the time course of the study. LLOQ, lower limit of quantification. , idrabiotaparinux; , idraparinux

Figure 6

Mean pharmacokinetic concentration vs. time profiles of idrabiotaparinux (3.0 mg) and idraparinux (2.5 mg) after single subcutaneous equimolar dosing in healthy volunteers (n = 24 per treatment group). LLOQ, lower limit of quantification. , idrabiotaparinux; , idraparinux

Figure 7

Pharmacokinetic concentrations vs. time profiles of idrabiotaparinux (3.0 mg) and its debiotinylated metabolite (SSR115771) vs. idraparinux (2.5 mg) after repeated subcutaneous equimolar dosing in patients in the EQUINOX bioequipotency substudy at month 6 (n = 114 per treatment group). , idrabiotaparinux and debiotinylated metabolite; , idraparinux

Figure 8

Predicted concentrations of idrabiotaparinux (3.0 mg) and its debiotinylated metabolite (SSR115771) vs. idraparinux (2.5 mg) after repeated subcutaneous equimolar dosing in patients over a 6 month treatment period. , idrabiotaparinux; , debiotinylated metabolite; , idraparinux