Human Pharmacokinetics and Pharmacodynamics of MF 701 Dermatan Sulfate Administered by Continuous Intravenous Infusion

Abstract

SummaryThe pharmacokinetics and haemostatic effects of MF 701 dermatan sulfate (DS) administered by i. v. infusion were studied in 11 healthy volunteers. Each subject received 0.6 mg kg-1 h-1 MF 701 for 10 h. DS plasma concentrations were measured by a chromogenic assay based on the catalysis of thrombin inhibition by HCII. DS plasma levels followed a single compartment pharmacokinetic model, with a half-life of 1.28 ± 0.46 h, a plasma clearance of 2.75 ± 0.46 1/h and a volume of distribution of 4.92 ± 1.36 1 (means ± SD). Steady-state was reached 3 to 6 h after infusion started. The maximal DS plasma concentration was 16.4 ± 5.7 μg/ml. Maximal APTT prolongation over pre-infusion values was 42 ± 7%; TCT performed with bovine and human thrombin was prolonged by 16 ± 7% and 83 ± 35% respectively. No anti-IIa or anti-Xa activities were detected by chromogenic tests. The treatment was well tolerated. The pharmacokinetics of MF 701 infusion are consistent with those previously described after i. v. bolus administration. The infusion of MF 701 allows fast achievement and steady maintenance of elevated DS plasma concentrations.

Intramuscular Dermatan Sulfate MF701 in Patients with Hip Fracture: Relationship between Pharmacokinetics and Antithrombotic Efficacy

“…First, the pharmacokinetic information provided by Dupouy's assay method appears to be relevant to the antithrombotic efficacy of MF701. This underlines the importance of pharmacokinetic data on MF701 obtained by this method in previous studies (12)(13)(14) and in the present one. Secondly, an increase of dermatan sulfate plasma levels to greater than 9 yglml may potentially result in a lower residual DVT rate than that observed in the present study [37.8% with 300 mg b. i. d. MF701 (8)]: without compromising safety.…”

“…Dermatan sulfate is known to be eliminated quickly from the bloodstream, as indicated by the elimination half-life of approximately 1 h estimated after intravenous administration (12)(13)(14). Therefore, the long apparent elimination half-life estimated in the present study (68 h or 43 h) was probably due to slow absorption of the drug from injection sites.…”

“…Conventional coagulation tests all have a low sensitivity to dermatan sulfate (2-4). Among them, TCT performed with human thrombin shows the best relative sensitivity both in vitro (4) and ex vivo in humans (8,12,13). In the present report the anticoagulant response to MF701.…”

The pharmacokinetics and pharmacodynamics of dermatan sulphate MF701 during haemodialysis for chronic renal failure.

“…The clearance of the drug during dialysis was 2.5 to 3.5 times slower, and the t½l, was accordingly longer, than in healthy subjects given 2-3 mg kg-' MF701 as an i.v. bolus or 6 mg kg-' as a 10-h infusion (Agnelli et al, 1990;Boneu et al, personal communication, 1990;Dawes et al, 1991;Dol et al, 1989). This finding is consistent with previous studies showing that renal excretion is the main route of elimination for MF701 in humans (Dawes et al, 1989), and that the clearance of the drug is impaired in nephrectomized rabbits .…”