Comparison of biological activities of two low molecular weight heparins in 10 healthy volunteers.
1. Low molecular weight heparins (LMWHs) are produced by different depolymerization processes and may therefore differ with respect to their pharmacokinetic properties. 2. We designed a single dose, randomized cross-over study in 10 healthy volunteers to compare the 24 h pharmacokinetics of two LMWHs, reviparin and enoxaparin, which have been previously shown to be clinically equivalent in terms of post-operative deep vein thrombosis prevention, despite significant differences in their in vivo biological activity. The two LMWHs were subcutaneously administered at the same dosages that are used in clinical studies: 4250 anti-Xa iu for reviparin and 40 mg for enoxaparin which have similar in vitro anti-Xa activities. 3. The overall 24 h profiles of the plasma anti-Xa and anti-thrombin activities were similar for reviparin and enoxaparin. The Amax and the AUC(0, 24h) of plasma anti-Xa activity after reviparin administration were both slightly but significantly lower than those observed after enoxaparin administration (difference between treatments of 0.03 95% CI[0.01-0.05] iu ml-1 h and 0.56 95% CI[0.22-0.90] iu ml-1 for Amax and AUC(0, 24h) respectively). After adjustment for in vitro anti-Xa activity, the statistical difference between the two LMWHs persisted for the AUC(0, 24h) but not for the Amax of plasma anti-Xa activity. The tmax and the MRT values for plasma anti-Xa activity did not significantly differ between the two drugs. The t1/2 for reviparin did not significantly differ from that of enoxaparin (2.7 +/- 0.7 h vs 3.5 +/- 0.9 h respectively, NS). The Amax of the plasma anti-thrombin activity after reviparin administration was also slightly but significantly lower than that observed after enoxaparin administration, (difference between treatments of 0.018 95% CI[0.01-0.025] iu ml-1) whereas the AUC(0, 24h) of anti-thrombin activity vs time was not. A slight but significant increase of the activated partial thromboplastin time of a similar magnitude was observed after both reviparin and enoxaparin injections. 4. The calculated surface under the thrombin generation curve vs time (or thrombin potential) at peak was significantly higher after reviparin than after enoxaparin (367 +/- 53 UA vs 305 +/- 48 UA respectively, P < 0.05). Four hours after injection, thrombin potential was significantly correlated to plasma anti-Xa activity after reviparin but not after enoxaparin injection (r = 0.65, n = 10, P = 0.05 and r = -0.38, n = 10, P = 0.25 respectively). 5. After a single-dose injection in healthy subjects, two LMWHs with comparable in vitro activities differed slightly kinetically. Such minor differences are probably of little importance in the prevention of post-operative deep vein thrombosis, since these two LMWHs were previously shown to be comparable in this setting.
Azizi
M
M
Centre d'Investigations Cliniques, Paris, France.
Veyssier-Belot
C
C
Alhenc-Gelas
M
M
Chatellier
G
G
Billaud-Mesguish
E
E
Fiessinger
J N
JN
Aiach
M
M
D000328:Adult; D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D017984:Enoxaparin / Q000097:blood / Q000493:pharmacokinetics*; D006495:Heparin, Low-Molecular-Weight / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D016037:Single-Blind Method
D000925:Anticoagulants; D017984:Enoxaparin; D006495:Heparin, Low-Molecular-Weight; C094240:reviparin