Comparative pharmacodynamic time-course of bemiparin and enoxaparin in healthy volunteers.
Low-molecular-weight heparins (LMWHs) are antithrombotic drugs that differ on biochemical and pharmacological properties.


OBJECTIVE
This study was conducted to compare the pharmacodynamic time-course of two LMWHs, bemiparin and enoxaparin, at high prophylactic doses.


METHODS
This was an open, randomized, single-blind, cross-over study to compare the pharmacodynamic time-course, safety and tolerability of two LMWHs, bemiparin 3500 IU and enoxaparin 4000 IU at subcutaneous single doses in 12 healthy male volunteers. Anti-Xa activity (main biomarker of heparin activity), anti-IIa activity, total and free tissue factor pathway inhibitor (TFPI), activated partial thromboplastin time (APTT), thrombin time (TT) and thromboplastin-thrombomodulin mediated time (Tp-TmT) were investigated.


RESULTS
Bemiparin 3500 IU achieved more anti-Xa activity than enoxaparin 4000 IU, measured by the area under the curve (geometric mean AUC0t) (bemiparin 3.69 vs. enoxaparin 3.33 IU h/ml; p < 0.001). Maximum anti-Xa activity was reached at 3 hours and there were anti-Xa measurable levels up to 16 h after subcutaneous administration. Anti-Xa activity half-life was 5.44 hours for bemiparin and 4.71 hours for enoxaparin. Anti-IIa activity was above the limit of quantification (0.05 IU/ml) in only 2 volunteers after bemiparin and in 8 after enoxaparin. The "in-vivo" anti-Xa:IIa ratios were: bemiparin 37.9 (95% CI: 28.0 - 55.3, n = 2) and enoxaparin 16.3 (95% CI: 12.2 - 23.4, n = 8). Enoxaparin induced a higher release of total TFPI, but not on free TFPI, and a longer prolongation of APTT and TT (Emax) than bemiparin, with no differences between groups on Tp-TmT. Adverse events (one in each group) were mild and transient.


CONCLUSIONS
Bemiparin 3500 IU showed more anti-Xa activity and higher anti-Xa: anti-IIa relationship than enoxaparin 4000 IU in healthy volunteers. Both treatments were well tolerated.
Antonijoan
R M
RM
Centre d' lnvestigació de Medicaments, Institut de Recerca, Servei de Farmacologia Clínica, Hospital de la Santa Creu i Sant Pau, Spain. rantonijoana@santpau.cat
Rico
S
S
Martínez-González
J
J
Borrell
M
M
Valcarcel
D
D
Fontcuberta
J
J
Barbanoj
M J
MJ
D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001779:Blood Coagulation Factors / Q000187:drug effects*; D001780:Blood Coagulation Tests; D018592:Cross-Over Studies; D017984:Enoxaparin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006495:Heparin, Low-Molecular-Weight / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D013997:Time Factors
D000925:Anticoagulants; D001779:Blood Coagulation Factors; D017984:Enoxaparin; D006495:Heparin, Low-Molecular-Weight; C411345:bemiparin