COMPARISON OF THE PHARMACOKINETIC PROFILES OF 3 LOW-MOLECULAR-MASS HEPARINS - DALTEPARIN, ENOXAPARIN AND NADROPARIN - ADMINISTERED SUBCUTANEOUSLY IN HEALTHY-VOLUNTEERS (DOSES FOR PREVENTION OF THROMBOEMBOLISM)

The present trial was designed to comparatively investigate the pharma cokinetic profile and evaluate the apparent bioavailability pattern of three already marketed low molecular mass heparins (LMMHs): daltepari n (Fragmin(R)), nadroparin (Fraxiparin(R)), and enoxaparin (Lovenox(R) ) given by subcutaneous route. The study was carried out in 20 healthy young volunteers given, according to a cross over design, a single su bcutaneous injection of the doses recommended for the prophylaxis of d eep vein thrombosis (commercial preparations, prefilled syringes): dal teparin 2,500 IU (= 2?500 IU anti-X(a)), nadroparin 7,500 ICU (= 3,075 IU anti-X(a)), enoxaparin 20 mg (= 2,000 IU anti-X(a)) and enoxaparin 40 mg (= 4,000 IU anti-X(a)). Of the markers used, activated partial thromboplastin time (APTT), thrombin clotting time (TCT), Heptest(R), anti-thrombin (aII(a)) activity and anti-X(a) (aX(a)) activity, the mo st pertinent parameter (from a biodynamic viewpoint) is plasma aX(a) a ctivity. We demonstrated that dalteparin, nadroparin and enoxaparin ex hibit statistically significantly different pharmacokinetic and overal l disposition patterns. Normalized to the same injected dose (1,000 IU aX(a)), the relative actual amount of plasma anti-X, activity generat ed by enoxaparin is 1.48 times greater (p < 0.001) than that of nadrop arin and 2.28 times greater (p < 0.001) than that of dalteparin while the plasma amount induced by nadroparin is 1.54 times greater (p < 0.0 01) than that of dalteparin. The apparent total body clearance of enox aparin doses (CL/F = 16.7 +/- 5.5 and 13.8 +/- 3.2 ml/min) is signific antly smaller than those of nadroparin (CL/F = 21.4 +/- 7.0 ml/min; p < 0.01) and dalteparin (CL/F = 33.3 +/- 11.8 ml/min; p < 0.001) while dalteparin apparent clearance is about 1.5-fold greater (p < 0.001) th an that of nadroparin. These LMMHs also differ by their renal excretio n pattern : mon fragments exhibiting an anti-lj activity are recovered in urine following enoxaparin doses (6.4 and 8.7 % of the dose, respe ctively) than following nadroparin (3.9 %) and dalteparin (3.4 %) inje ction. These differences in the disposition profiles explain why the a pparent elimination half life t(1/2) values of the LMMHs compared here are different: dalteparin: 2.8 h; nadroparin: 3.7 h; and enoxaparin: 4.1 h. Whether or not these differences may contribute to explain the different safety/efficacy balance of each of these antithrombotic medi cations remains to be discussed and needs further studies.