Pharmacokinetics and Tolerance of the Natural Pentasaccharide (SR90107/ORG31540) with High Affinity to Antithrombin III in Man

Summary

This paper reports the results of the first administration of the synthetic natural pentasaccharide with high affinity to antithrombin III (NP) in man. The study was mainly focused upon the pharmacokinetic properties and general tolerance of the compound. Subcutaneous injections of doses <1.43 mg (1000 anti Xa IU) did not generate measurable anti-Xa activities. After subcutaneous injection of increasing doses from 1.43 to 22.9 mg (1000 to 16000 anti-Xa IU) to young healthy volunteers, it was found that the maximal concentration (C_max) and the area under curve (AUC) were linearly correlated to the dose, that the total plasma clearances (Cl) were constant and almost 3 times lower than those of the current low molecular weight heparins. Cmax were reached between 1 h and 3 h after the injection and the half-lives (t_1/2) were remarkably constant (13.1 h to 13.9 h). During the first 24 h following the injection, around 50% of the total administered dose was recovered in the urine in an active form, indicating that kidney plays a major role in the elimination of NP. Consistent with these results, when NP was administered to healthy elderly volunteers having a lower creatinine clearance, the half-life of the compound was longer and the clearance lower. At doses exceeding 22.9 mg, C_max, and AUC were slightly lower than expected, the percentage of the dose recovered in the urine and the total apparent plasma clearance increased, suggesting that the excess of NP unbound to antithrombin III was excreted faster. NP was also administered at various dosages once or twice a day for 7 days to 20 elderly volunteers. Due to the long half-life of the compound the “steady state” was obtained 2 to 3 days after the first injection at which the mean C_max was increased 1.5 to 2 times. The general tolerance of the compound was excellent. No relevant prolongations of the prothrombin time, of the activated partial thromboplastin time or of the bleeding time were observed. A re-bleeding phenomenon of the bleeding time incision, probably related to friability of the haemostatic plug, occurred in 3 subjects treated with the highest dose regimens: single injection of 26.6 mg (20000 anti-Xa IU) (young volunteers) and repeated injections of 11.4 mg (8000 anti-XaIU) once a day for 7 days (elderly volunteers). At these times, plasma NP concentrations were between 2.9 and 3.6 μg ⋅ ml^-1 (2 and 2.5 anti-Xa IU ⋅ ml^-1).

• References

• 1 Hirsh J. Heparin. New Engl J Med 1991; 324: 1565-1574
• 2 Choay J, Lormeau JC, Petitou M, Sinaÿ P, Fareed J. Structural studies on a biologically active hexasaccharide obtained from heparin. Ann NY Acad Sci 1981; 370: 644-649
• 3 van Boeckel CA A, Beetz T, Vos JN, de Jong AJ M, van Aelst SF, van der Bosch RH, Mertens JM R, van der Vlugt FA. Synthesis of a pentasaccharide corresponding to the antithrombin III binding fragment of heparin. J Carbohydr Chem 1985; 4: 293-321
• 4 Sinaÿ P, Jacquinet J, Petitou M, Duchaussoy P, Lederman I, Choay J, Torri G. Total synthesis of a heparin pentasaccharide fragment having high affinity for antithrombin III. Carbohydr Res 1984; 132: C5-C9
• 5 Choay J, Petitou M, Lormeau JC, Sinaÿ P, Casu BJ, Gatti G. Structure-activity of relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin III and eliciting high antifactor Xa activity. Bio chem Biophys Res Com 1983; 116: 492-499
• 6 Béguin S, Choay J, Hemker HC. The action of a synthetic pentasaccharide on thrombin generation in whole plasma. Thromb Haemost 1989; 61: 397-401
• 7 Lormeau JC, Herault JP. Comparative inhibition of extrinsic and intrinsic thrombin generation by standard heparin, a low molecular weight heparin and the synthetic ATIII-binding pentasaccharide. Thromb Haemost 1993; 69: 152-156
• 8 Walenga JM, Fareed J, Petitou M, Samama M, Lormeau JC, Choay J. Intravenous antithrombotic activity of a synthetic heparin pentasaccharide in a human serum induced stasis thrombosis model. Thromb Res 1986; 43: 243-248
• 9 Walenga JM, Petitou M, Lormeau JC, Samama M, Fareed J, Choay J. Antithrombotic activity of a synthetic heparin pentasaccharide in a rabbit stasis thrombosis model using different thrombogenic challenges. Thromb Res 1987; 46: 187-198
• 10 Thomas DP, Merton RE, Gray E, Barrowcliffe TW. The relative antithrombotic effectiveness of heparin, a low molecular weight heparin, and a pentasaccharide fragment in an animal model. Thromb Haemost 1989; 61: 204-207
• 11 Amar J, Caranobe C, Sié P, Boneu B. Antithrombotic potencies of heparins in relation to their antifactor Xa and antithrombin activities: an experimental study in two models of thrombosis in the rabbit. Br J Haematol 1990; 76: 94-100
• 12 Hobbelen PM J, van Dinther TG, Vogel GM T, van Boeckel CA A, Moelker HC T, Meuleman DG. Pharmacological profile of the chemically synthesized antithrombin III binding fragment of heparin (pentasaccharide) in rats. Thromb Haemost 1990; 63: 265-270
• 13 Vogel GM T, van Amsterdam RG M, Kop WJ, Meuleman DG. Pentasaccharide and Orgaran arrest, whereas heparin delays thrombus formation in a rat arteriovenous shunt. Thromb Haemost 1993; 69: 29-34
• 14 Cadroy Y, Hanson SR, Harker LA. Antithrombotic effects of synthetic pentasaccharide with high affinity for plasma antithrombin III in non-human primates. Thromb Haemost 1993; 70: 631-635
• 15 Carrié D, Caranobe C, Saivin S, Houin G, Petitou Lormeau JC, van Boeckel C, Meuleman D, Boneu B. Pharmacokinetic and antithrombotic properties of two pentasaccharides with high affinity to antithrombin III in the rabbit: comparison with CY216. Blood 1994; 84: 2571-2577
• 16 Briant L, Caranobe C, Saivin S, Sié P, Bayrou B, Houin G, Boneu B. Unfractionated heparin and CY 216 pharmacokinetics and bioavailabilities of the antifactor Xa and Ha effects after intravenous and subcutaneous injection in the rabbit. Thromb Haemost 1989; 61: 348-353
• 17 Frydman AM, Bara L, Le Roux Y, Woler M, Chauliac F, Samama MM. The antithrombotic activity and pharmacokinetics of enoxaparin, a low molecular weight heparin, in humans given single subcutaneous doses of 20 to 80 mg. J Clin Pharmacol 1988; 28: 609-618
• 18 Rostin M, Montastruc JL, Houin G, D’Azemar P, Bayrou B, Boneu B. Pharmacodynamics of CY216 in healthy volunteers: inter-individual variations. Fund Clin Pharmacol 1990; 4: 17-23
• 19 Bratt G, Törnbohm E, Widlund L, Lockner D. Low molecular weight heparin (Kahi 2165, fragmin): pharmacokinetics after intravenous and subcutaneous administration in human volunteers. Thromb Res 1986; 42: 613-620
• 20 Cadroy Y, Pourral J, Baladre MF, Saivin S, Houin G, Montastrue JL, Vernier I, Boneu B. Delayed elimination of enoxaparine in patients with chronic renal insufficiency. Thromb Res 1991; 63: 385-390
• 21 Goudable C, Saivin S, Houin G, Sié P, Boneu B, Ton That H, Sue JM. Pharmacokinetics of a low molecular weight heparin (Fraxiparin¹⁰) in various stages of chronic renal failure. Nephron 1991; 59: 543-545
• 22 Caranobe C, Petitou M, Dupouy D, Gabaig AM, Sié P, Buchanan MR, Boneu B. Heparin fractions with high and low affinities to antithrombin III are cleared at different rates. Thromb Res 1986; 43: 635-641
• 23 Palm M, Matsson C. Pharmacokinetics of Fragmin: a comparative study in the rabbit of its high and low affinity to antithrombin. Thromb Res 1987; 48: 51-62
• 24 Peyrou V, Lormeau JC, Caranobe C, Gabaig AM, Crepon B, Saivin S, Houin G, Sié P, Boneu B. Pharmacological properties of CY2I6 and of its ACLM and BCLM components in the rabbit. Thromb Maemost 1994; 72: 268-274