Pharmacokinetic considerations on Orgaran (Org 10172) therapy.
Pharmacokinetic investigations on Orgaran (Org 10172) have been conducted by monitoring the following biological effects: plasma anti-Xa, anti-IIa and IIa-generation-inhibiting (IIaGI) activities. In addition, a limited number of studies were conducted on the basis of concentrations of the No-affinity glycosaminoglyc(uron)an (NoA-GAG) fraction as determined by a competitive binding assay. In humans, widely different pharmacokinetic profiles for various biological effects were observed, with relatively short elimination half-lives for the anti-IIa and IIaGI activities of 4.3 +/- 3.5 and 6.7 +/- 3.2 h, respectively, but a relatively long elimination half-life of anti-Xa activity of 24.5 +/- 9.6 h. These differences in half-life mainly reflect differences in the rate of elimination of individual components of Orgaran. Rapid elimination of some of these components may explain why twice daily dosing is required for optimal thrombosis prophylaxis with Orgaran. In a comparative study in healthy male volunteers, the pharmacokinetics of the following low molecular weight heparin(oid)s were determined after intravenous administration: Orgaran (3,750 anti-Xa units), Fragmin (5,000 anti-Xa units), Fraxiparine (7,500 IC units) and Clexane (40 mg). Between these products, wide differences in pharmacokinetics were observed. Particularly, the half-lives of anti-Xa activity and IIaGI activity were much longer for Orgaran than for the other products. At the same time, a relatively low area under the curve of anti-IIa activity was observed. The absolute bioavailability of Orgaran following subcutaneous administration was determined on the basis of plasma anti-Xa and IIaGI activities and the NoA-GAG fraction concentrations. Absorption from subcutaneous tissues was found to be close to 100%, which is significantly higher than of heparin; a finding which indicates that the subcutaneous route is reliable for the administration of Orgaran. The elimination of Orgaran components occurs by renal and possibly non-renal routes. With respect to anti-Xa activity, about 50% of the total clearance can be accounted for by urinary excretion. Therefore, in severe renal failure, a reduction of the maintenance dose of Orgaran would seem to be indicated. Studies on the influence of enzyme induction as a result of treatment with pentobarbital suggest that the pharmacokinetics of Lomoparan are relatively insensitive to changes in hepatic function. In a number of studies, the influence of conditions such as age, body weight and drug interactions were studied. Generally, only minor changes in the pharmacokinetic parameters of Orgaran were observed.(ABSTRACT TRUNCATED AT 400 WORDS)
Danhof
M
M
Center for Bio-Pharmaceutical Sciences, University of Leiden, The Netherlands.
de Boer
A
A
Magnani
H N
HN
Stiekema
J C
JC
D000328:Adult; D000368:Aged; D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D002809:Chondroitin Sulfates; D003871:Dermatan Sulfate; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D065427:Factor Xa Inhibitors; D005260:Female; D006025:Glycosaminoglycans / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006207:Half-Life; D006495:Heparin, Low-Molecular-Weight / Q000493:pharmacokinetics / Q000627:therapeutic use; D006496:Heparinoids / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006497:Heparan Sulfate; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011516:Prothrombin / Q000037:antagonists & inhibitors; D051381:Rats; D013927:Thrombosis / Q000517:prevention & control
D002809:Chondroitin Sulfates; D003871:Dermatan Sulfate; D065427:Factor Xa Inhibitors; D006025:Glycosaminoglycans; D006495:Heparin, Low-Molecular-Weight; D006496:Heparinoids; D006497:Heparan Sulfate; D011516:Prothrombin; C025337:Factor IIa; C035838:danaparoid