Clinical Drug Investigation

, Volume 23, Issue 8, pp 533–543 | Cite as

Pharmacokinetics and Pharmacodynamics of Intramuscular Dermatan Sulfate Revisited

A Single- and Repeated-Dose Study in Healthy Volunteers
  • Sylvie Saivin
  • Jean-Pierre Cambus
  • Claire Thalamus
  • Geneviève Lau
  • Bernard Boneu
  • Georges Houin
  • Francesco Gianese
Original Research Article

Abstract

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.

Keywords

Dermatan Sulfate Intramuscular Dose Pentosan Polysulfate Human Thrombin Single Intramuscular Injection 

Notes

Acknowledgements

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.

References

  1. 1.
    Tollefsen DM. Insight into the mechanism of action of heparin cofactor II. Thromb Haemost 1995; 74: 1209–14PubMedGoogle Scholar
  2. 2.
    Bendayan P, Boccalon H, Dupouy D, et al. Dermatan sulfate is a more potent inhibitor of clot-bound thrombin than unfractionated and low molecular weight heparins. Thromb Haemost 1994; 71: 576–80PubMedGoogle Scholar
  3. 3.
    Agnelli G, Gianese F. Dermatan sulfate: biological and pharmacological properties; clinical applications. In: Goldhaber SZ, editor. Prevention of venous thromboembolism. New York: Marcel Dekker, 1993: 287–313Google Scholar
  4. 4.
    Prandoni P, Meduri F, Cuppini S, et al. Dermatan sulfate: a safe approach to prevention of postoperative deep vein thrombosis. Br J Surg 1992; 79: 505–9PubMedCrossRefGoogle Scholar
  5. 5.
    Cohen AT, Phillips MJ, Edmondson RA, et al. A dose ranging study to evaluate dermatan sulphate in preventing deep vein thrombosis following total hip arthroplasty. Thromb Haemost 1994; 72: 793–8PubMedGoogle Scholar
  6. 6.
    Agnelli G, Cosmi B, Di Filippo P, et al. A randomised, double-blind, placebo-controlled trial of dermatan sulphate for prevention of deep vein thrombosis in hip fracture. Thromb Haemost 1992; 67: 203–8PubMedGoogle Scholar
  7. 7.
    Di Carlo V, Agnelli G, Prandoni P, et al. Dermatan sulphate for the prevention of postoperative venous thromboembolism in patients with cancer. Thromb Haemost 1999; 82: 30–4Google Scholar
  8. 8.
    Dawes J, Hodson BA, Pepper DS. The absorption, clearance and metabolic fate of dermatan sulfate administered to man: studies using a radioiodinated derivative. Thromb Haemost 1989; 62: 945–9PubMedGoogle Scholar
  9. 9.
    Dol F, Houin G, Rostin M, et al. Pharmacodynamics and pharmacokinetics of dermatan sulfate in humans. Blood 1989; 74: 1577–82PubMedGoogle Scholar
  10. 10.
    Dawes J, McLaren M, Forbes C, et al. The pharmacokinetics of dermatan sulphate MF701 in healthy human volunteers. Br J Clin Pharmacol 1991; 32: 361–6PubMedCrossRefGoogle Scholar
  11. 11.
    Boneu B, Sié P, Houin G. Report of Mediolanum study 701P06. Toulouse, France: CHU Purpan, 1990Google Scholar
  12. 12.
    Agnelli G, Cosmi B, Renga C, et al. Human pharmacokinetics and pharmacodynamics of MF701 dermatan sulfate administered by continuous intravenous infusion. Thromb Haemost 1990; 64: 256–9PubMedGoogle Scholar
  13. 13.
    Borg JY, Chrétien MH, Doucet J, et al. Pharmacokinetics and haemostatic effects of dermatan sulfate (DS, Mediolanum Farmaceutici) administered by intravenous infusion in elderly volunteers [abstract]. Thromb Haemost 1993; 69: 1320Google Scholar
  14. 14.
    Imbimbo BP, Sié P, Agnelli G, et al. Intramuscular dermatan sulfate MF701 in patients with hip fracture: relationship between pharmacokinetics and antithrombotic efficacy. Thromb Haemost 1994; 71: 553–7PubMedGoogle Scholar
  15. 15.
    Dupouy D, Sié P, Dol F, et al. A simple method to measure dermatan sulfate at submicrogram concentrations in plasma. Thromb Haemost 1988; 60: 236–9PubMedGoogle Scholar
  16. 16.
    Colibretti ML, Lamperti MP. Report of Mediolanum study RB/ 007–98. Milan, Italy: Mediolanum Farmaceutici, 1998Google Scholar
  17. 17.
    Iorio A, Nucciarelli F, Renga C, et al. Effects of dermatan sulphate on activated partial thromboplastin time determined with different reagents. Haemostasis 1997; 27: 85–90PubMedGoogle Scholar
  18. 18.
    Gomeni R. PHARM: an interactive graphic program for individual and population pharmacokinetic parameter estimation. Comput Biol Med 1984; 14: 25–34PubMedCrossRefGoogle Scholar
  19. 19.
    Cockroft DW, Gault MM. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41CrossRefGoogle Scholar
  20. 20.
    Dol F, Houin G, Dupouy D, et al. Pharmacokinetics of dermatan sulfate in the rabbit after intravenous injection. Thromb Haemost 1988; 59: 255–8PubMedGoogle Scholar
  21. 21.
    Harenberg J, Jeschek M, Acker M, et al. Effects of low-molecular-weight dermatan sulfate on coagulation, fibrinolysis and tissue factor pathway inhibitor in healthy volunteers. Blood Coagul Fibrinolysis 1996; 7: 49–56PubMedCrossRefGoogle Scholar
  22. 22.
    Saivin S, Dol F, Caranobe C, et al. Influence of molecular weight upon the anticoagulant and pharmacokinetic properties of dermatan sulfate in the rabbit. Thromb Res 1992; 66: 527–35PubMedCrossRefGoogle Scholar
  23. 23.
    Toulemonde F, Kher A. Héparines et transaminases: une énigme sans importance en 1994? Thérapie 1994; 49: 356–8PubMedGoogle Scholar
  24. 24.
    Frydman A. Low-molecular-weight heparins: an overview of their pharmacodynamics, pharmacokinetics and metabolism in humans. Haemostasis 1996; 26 Suppl. 2: 24–38PubMedGoogle Scholar
  25. 25.
    Hull RD, Pineo GF, Stein PD, et al. Timing of initial administration of low-molecular-weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty. Arch Intern Med 2001; 161: 1952–60PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  • Sylvie Saivin
    • 1
    • 2
  • Jean-Pierre Cambus
    • 3
  • Claire Thalamus
    • 4
  • Geneviève Lau
    • 4
  • Bernard Boneu
    • 3
  • Georges Houin
    • 1
    • 2
  • Francesco Gianese
    • 5
  1. 1.Cinétique des Xénobiotiques, Faculté des Sciences PharmaceutiquesToulouseFrance
  2. 2.Laboratoire de Pharmacocinétique et Toxicologie CliniqueCHU RangueilToulouseFrance
  3. 3.Laboratoire de Recherche sur l’Hémostase et la ThromboseCHU PurpanToulouseFrance
  4. 4.Centre d’Investigation CliniqueCHU PurpanToulouseFrance
  5. 5.Medical DepartmentMediolanum Farmaceutici SpAMilanoItaly

Personalised recommendations