Bioequipotency of idraparinux and idrabiotaparinux after once weekly dosing in healthy volunteers and patients treated for acute deep vein thrombosis.
OBJECTIVE
To assess the bioequipotency of equimolar doses of idraparinux (2.5 mg) and idrabiotaparinux (3.0 mg).


METHODS
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.


CONCLUSIONS
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.
Research and Development, Sanofi, Chilly-Mazarin, France. marc.trellu@sanofi.com
Marc
M
Trellu
Jean-Baptiste
JB
Fau
Pierre
P
Cortez
Sue
S
Cheng
Isabelle
I
Paty
Emmanuelle
E
Boëlle
François
F
Donat
Ger-Jan
GJ
Sanderink
D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001710:Biotin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D006801:Humans; D008297:Male; D008875:Middle Aged; D009844:Oligosaccharides / Q000493:pharmacokinetics* / Q000494:pharmacology; D013810:Therapeutic Equivalency; D020246:Venous Thrombosis / Q000188:drug therapy* / Q000378:metabolism; D055815:Young Adult
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D009844:Oligosaccharides; C479958:idraparinux; D001710:Biotin; D015951:Factor Xa; C545956:idrabiotaparinux