Comparison of the Pharmacokinetic Profiles of Three Low Molecular Mass Heparins – Dalteparin, Enoxaparin and Nadroparin – Administered Subcutaneously in Healthy Volunteers (Doses for Prevention of Thromboembolism)

F Collignon; A Frydman; H Caplain; M L Ozoux; Y Le Roux; J Bouthier; J J Thébault

doi:10.1055/s-0038-1653833

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1995; 73(04): 630-640
DOI: 10.1055/s-0038-1653833

Original Articles

Coagulation

Schattauer GmbH Stuttgart

Comparison of the Pharmacokinetic Profiles of Three Low Molecular Mass Heparins – Dalteparin, Enoxaparin and Nadroparin – Administered Subcutaneously in Healthy Volunteers (Doses for Prevention of Thromboembolism)

F Collignon

¹Rhône-Poulenc Rorer S.A., Institut de Biopharmacie, Department of Biodynamics, Paris, France

,

A Frydman

¹Rhône-Poulenc Rorer S.A., Institut de Biopharmacie, Department of Biodynamics, Paris, France

,

H Caplain

²Institut Aster, Hopital Cognacq-Jay, Paris, France

,

M L Ozoux

¹Rhône-Poulenc Rorer S.A., Institut de Biopharmacie, Department of Biodynamics, Paris, France

,

Y Le Roux

¹Rhône-Poulenc Rorer S.A., Institut de Biopharmacie, Department of Biodynamics, Paris, France

,

J Bouthier

³Rhône-Poulenc Rorer S.A., Medical Affairs, Antony, Paris, France

,

J J Thébault

²Institut Aster, Hopital Cognacq-Jay, Paris, France

› Institutsangaben

Abstract

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Summary

The present trial was designed to comparatively investigate the pharmacokinetic profile and evaluate the apparent bioavailability pattern of three already marketed low molecular mass heparins (LMMHs): dalteparin (Fragmin®), nadroparin (Fraxiparin®), and enoxaparin (Love- nox®) given by subcutaneous route. The study was carried out in 20 healthy young volunteers given, according to a cross over design, a single subcutaneous injection of the doses recommended for the prophylaxis of deep vein thrombosis (commercial preparations, prefilled syringes): dalteparin 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®, anti-thrombin (aII_a) activity and anti-X_a (aX_a) activity, the most pertinent parameter (from a biodynamic viewpoint) is plasma aX_a activity. We demonstrated that dalteparin, nadroparin and enoxaparin exhibit statistically significantly different pharmacokinetic and overall disposition patterns. Normalized to the same injected dose (1,000 IU aX_a), the relative actual amount of plasma anti-X_a activity generated by enoxaparin is 1.48 times greater (p < 0.001) than that of nadroparin 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 < 0.001) than that of dalteparin. The apparent total body clearance of enoxaparin doses (CL/F = 16.7 ± 5.5 and 13.8 ± 3.2 ml/min) is significantly 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) than that of nadroparin. These LMMHs also differ by their renal excretion pattern : more fragments exhibiting an anti-X_a activity are recovered in urine following enoxaparin doses (6.4 and 8.7 % of the dose, respectively) than following nadroparin (3.9 %) and dalteparin (3.4 %) injection. These differences in the disposition profiles explain why the apparent 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 medications remains to be discussed and needs further studies.

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Referenzen

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