PHARMACOKINETICS AND TOLERANCE OF THE NATURAL PENTASACCHARIDE (SR90107 ORG31540) WITH HIGH-AFFINITY TO ANTITHROMBIN-III IN MAN/

This paper reports the results of the first administration of the synt hetic natural pentasaccharide with high affinity to antithrombin III ( NP) in man. The study was mainly focused upon the pharmacokinetic prop erties 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 1.4 3 to 22.9 mg (1000 to 16000 anti-Xa IU) to young healthy volunteers, i t was found that the maximal concentration (C-max) andtire area under curve (AUG) were linearly correlated to the dose, that the total plasm a clearances (Cl) were constant and almost 3 times lower than those of the current low molecular weight heparins. C-max were reached between 1 h and 3 h after the injection and the half-lives (t(1/2)) were rema rkably constant(l3.1 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 rol e 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 t he total apparent plasma clearance increased, suggesting that the exce ss 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 e lderly volunteers. Due to the long half-life of the compound the ''ste ady state'' was obtained 2 to 3 days after the First injection at whic h the mean C-max was increased 1.5 to 2 times. The general tolerance o f the compound was excellent. No relevant prolongations of the prothro mbin time, of the activated partial thromboplastin time or of the blee ding time were observed. A re-bleeding phenomenon of the bleeding time incision, probably related to friability of the haemostatic plug, occ urred in 3 subjects treated with the highest dose regimens: single inj ection of 26.6 mg (20000 anti-Xa IU) (young volunteers) and repeated i njections of 11.4 mg (8000 anti-Xa IU) once a day for 7 days (elderly volunteers). At these times, plasma WP concentrations were between 2.9 acid 3.6 mu g . ml(-1) (2 and 2.5 anti-Xa IU . ml(-1)).