Objective: To assess the pharmacokinetics and effects on blood coagulation of dermatan sulfate (DS), a glycosaminoglycan with antithrombotic properties, following intravenous and single and repeated intramuscular administrations. The mean molecular weight of DS is currently 22kD, i.e. 5kD lower than batches used in the early development of the compound.
Subjects and methods: Each of 14 male healthy volunteers received DS 300mg as an 8-hour intravenous infusion and as single and repeated (once daily for 9 days) intramuscular injections. Nine of the same subjects were also given DS 100mg and 200mg as single intramuscular doses. Plasma DS concentrations were measured with a specific chromogenic assay. Activated partial thromboplastin time (aPTT) and thrombin clotting time (TCT) responses were also determined.
Results: The mean ± SD volume of distribution and terminal half-life of DS were 6.0 ± 1.4L and 0.9 ± 0.2h after intravenous infusion. Maximum plasma concentration (Cmax) and area under the plasma concentration-time curve after single intramuscular injections were dose-proportional. After repeated intramuscular administration, steady state was reached by day 3. On day 9, plasma DS fluctuated between 4.3 ± 1.5 (Cmax) and 0.9 ± 0.4 (minimum plasma concentration at steady state) mg/L, time to Cmax was 3.4 ± 0.8h, terminal half-life was 12.2 ± 4.1h and the accumulation factor was 2.0 ± 0.5. Geometric mean bioavailability of intramuscular DS was 54% and 79% after single and repeated 300mg administration, respectively. aPTT and TCT responses were both linearly related to plasma DS concentrations, with TCT showing greater responsivity.
Conclusion: As compared with earlier DS studies, the present data showed a greater extent of DS absorption after single intramuscular administration and a faster absorption rate after repeated dosing, and provided evidence of dose-response predictability. These findings may explain the improved antithrombotic efficacy of DS observed in a recent clinical trial.
Dermatan Sulfate Intramuscular Dose Pentosan Polysulfate Human Thrombin Single Intramuscular Injection
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We thank A.M. Gabaig (Toulouse, France) and A. Maggi (Milan, Italy) for their respective contributions to assay work and study monitoring. Assay data and pharmacokinetic calculations were audited by F. Nguyen and M. Lavit (Toulouse, France). Safety data were analysed by L. Santoro (Milan, Italy). Dr F. Gianese is an employee of Mediolanum Farmaceutici; he does not own stock or hold any options to purchase stock in the company. The study was supported in part by a grant from Mediolanum Farmaceutici.
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