Unfractionated Heparin and CY 216: Pharmacokinetics and Bioavailabilities of the Antifactor Xa and IIa Effects after lntravenous and Subcutaneous Injection in the Rabbit

Summary

This report compares the pharmacokinetics and the bioavailabilities of the antifactor Xa and of the antifactor II a activities generated by intravenous (IV) and subcutaneous (SC) injections of increasing doses of unfractionated heparin (UH) and of a low molecular weight heparin (CY 216). Rabbits were injected with 500, 1,000, 2,500 and 5,000 antifactor Xa u/kg of both heparins and their biological activities were followed at various time intervals. After IV injection the clearance of the antifactor Xa activities was independent of the dose and the clearance of UH was significantly higher than that of CY 216; after SC injection the bioavailability estimated from the antifactor Xa effect was consistently over 100% for CY 216 while that of UH increased from 27% at the lowest dose to 93% at the highest dose. The pharmacokinetic parameters estimated by the antifactor IIa activity of UH were superimposable to those calculated with the antifactor Xa activity. For CY 216 no direct comparison between the two activities was made since the dose injected expressed in antifactor IIa units was 3.4 times lower. UH and CY 216 were therefore injected intravenously to other animals at equivalent and increasing doses expressed in antifactor IIa units (50-5,000 u/kg). The pharmacokinetic parameters calculated from the curves of the antifactor IIa activities were basically identical except at the two lower doses (50 and 100 u/kg) for which UH was cleared faster than CY 216. These results indicate that the antifactor IIa activity generated by an injection of CY 216 disappears faster than the corresponding antifactor Xa activity and therefore that the antifactor Xa/antifactor IIa activity ratio of CY 216 progressively increases after SC or IV injection.

Keywords

Unfractionated heparin - Low molecular weight heparin - CY 216 - Fraxiparine^® - Pharmacokinetics

• References

• 1 Bara L, Billaud E, Kher A, Samama M. Increased anti-Xa bioavailability for a low molecular weight heparin (PK 10169) compared with infractionated heparin. Sem Thromb Hemostas 1985; 11: 316-317
• 2 Dawes J, Bara L, Billaud E, Samama M. Relationship between biological activity and concentration of a low-molecular-weight heparin (PK 10169) and unfractionated heparin after intravenous and subcutaneous administration. Haemostasis 1986; 16: 116-122
• 3 Harenberg J, Wϋrzner B, Zimmermann R, Schettler G. Bioavailability and antagonization of the low molecular weight heparin CY 216 in man. Thromb Res 1986; 44: 549-554
• 4 Dawes J, Prowse CV, Pepper DS. Absorption of heparin, LMW heparin and SP 54 after subcutaneous injection assessed by competitive binding assay. Thromb Res 1986; 44: 683-693
• 5 Emanuele RM, Fareed J. The effect of molecular weight on the bioavailability of heparin. Thromb Res 1987; 48: 591-596
• 6 Bentley PG, Kakkar V, Scully MF, McGregor IR, Webb P, Chan P, Jones N. An objective study of alternative methods of heparin administration. Thromb Res 1980; 18: 177-187
• 7 Andersson G, Fagrell B, Holmgren K, Johnson H, Ljunberg J, Nilsson E, Vilhemson S, Zetterquist S. Subcutaneous administration of heparin: a randomized comparison with intravenous administration of heparin to patients with deep vein thrombosis. Thromb Res 1982; 27: 631-639
• 8 Doyle DJ, Turpie AG G, Hirsh ChB, Best C, Kinch D, Levine MN, Gent M. Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis. Ann Intern Med 1987; 107: 441-445
• 9 Faivre R, Neuhart Y, Kieffer Y, Apfel F, Magnin D, Didier D, Toulemonde F, Bassand JP, Maurat JP. Un nouveau traitement des thromboses veineuse profondes: les fractions d’héparine de bas poids moléculaire. Presse Med 1988; 17: 197-200
• 10 Dupouy D, Sieé P, Dol F, Boneu B. A simple method to measure dermatan sulfate at sub-microgram concentrations in plasma. Thromb Haemostas 1988; 60: 236-239
• 11 Boneu B, Caranobe C, Gabaig AM, Dupouy D, Sie P, Buchanan MR, Hirsh J. Evidence for a saturable mechanism of disappearance of standard heparin in rabbits. Thromb Res 1987; 46: 835-844
• 12 Benchekroun S, Eychenne B, Mericq O, Colombani A, Douste-Blazy Ph, Barret A, Sie P, Boneu B. Heparin half-life and sensitivity in normal subjects and in patients affected by deep vein thrombosis. Eur J Clin Invest 1986; 16: 536-539
• 13 Bjornsson TD, Wolfram KM, Kitchell BB. Heparin kinetics determined by three assay method. Clin Pharmacol Ther 1982; 31: 104-113
• 14 Bratt G, Tömebohm E, Lockner D, Bergström K. A human pharmacological study comparing conventional heparin and a low molecular weight heparin fragment. Thromb Haemostas 1985; 53: 208-211
• 15 Boneu B, Buchanan MR, Caranobe C, Gabaig AM, Dupouy D, Sié P, Hirsh J. The disappearance of a low molecular weight heparin (CY 216) differs from standard heparin in rabbits. Thromb Res 1987; 46: 845-853
• 16 Olsson P, Lagergren H, Ek S. The elimination from plasma of intravenous heparin. An experimental study on dogs and humans. Acta Med Scand 1963; 173: 619-630
• 17 Estes JW. Kinetics of the anticoagulant effect of heparin. JAMA 1970; 212: 1492-1495
• 18 Bjomsson TD, Levy GP. Pharmacokinetics of heparin. I. Studies of dose dependence in rats. J Pharmacol Exp Ther 1979; 210: 237-242
• 19 De Swart CA M, Nijmeyer B, Roelofs JM M, Sixma JJ. Kinetics of intravenously administered heparin in normal humans. Blood 1982; 60: 1251-1258
• 20 Piper J. The fate of heparin in rabbits after intravenous injection. Filtration and tubular secretions in the kidneys Acta Pharmacol 1947; 3: 373-384
• 21 Caranobe C, Barret A, Gabaig AM, Dupouy D, Sié P, Boneu B. Disappearance of circulating anti-Xa activity after intravenous injection of standard heparin and of a low molecular weight heparin (CY 216) in normal and nephectomized rabbits. Thromb Res 1985; 40: 129-133
• 22 Goudable C, Ton That H, Damani A, Durand S, Caranobe C, Sié P, Boneu B. Low molecular weight heparin half life is prolonged in haemodialysed patients. Thromb Res 1986; 43: 1-5
• 23 Williams SV, Barrowcliffe TW. The effects of post heparin plasma lipases on anti-Xa clotting activity. Thromb Res 1985; 37: 371-377
• 24 Cambus JP, Toulemonde F, Bayrou B, Bierme R. Anti Xa-anti IIa ratio variations for VLMW heparin fragment. A study in healthy volunteers (abstr). In: Xth International Congress on Thrombosis: The Mediterranean League against Thromboembolic Diseases. Athens: 05/1988. Abstract book p 104
• 25 Buchanan MR, Boneu B, Ofosu F, Hirsh J. The relative importance of thrombin inhibition and factor Xa inhibition to antithrombotic effects of heparin. Blood 1985; 65: 198-201