Journal of Pharmaceutical Investigation

The Korean Society of Pharmaceutical Sciences and Technology (한국약제학회)
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Pharmacokinetic-Pharmacodynamic Modeling of a Direct Thrombin Inhibitor, Argatroban, in Rats

  • Published : 2009.10.20
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Abstract

This study was conducted to develop a pharmacokinetic-pharmacodynamic (PK/PD) model of a direct thrombin inhibitor, argatroban to predict the concentration-effect profiles in rats. Argatroban was i.v. injected to rats at 0. 2, 0.8 and 3.2 mg/kg doses (n = 4-5 per dose), and plasma drug levels were determined by a validated LC/MS/MS assay. The pharmacokinetics of argatroban was linear over the i.v. dose range studied. The thrombin time (TT) and the activated partial thromboplastin time (aPTT) were measured in rat plasma and they were found to linearly increase with increasing the dose. A 2-compartment pharmacokinetic model linked with an indirect response pharmacodynamic model was successfully utilized to evaluate the drug concentration-response relationship.

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References

  1. L.R. Bush, Argatroban, a selective, potent thrombin inhibitor, Cardiovas. Drug Rev., 9, 247-263 (1991). https://doi.org/10.1111/j.1527-3466.1991.tb00415.x
  2. T. Tamao, T. Yamamoto, T. Hirata, M. Kinusaga and R. Kikumoto, Effect of argatroban on blood coagulation, Jap. J. Pharm. Ther., 14, 7-12 (1986).
  3. K. McKeage and G.L. Plosker, Argatroban, Drugs, 61, 515-522 (2001). https://doi.org/10.2165/00003495-200161040-00005
  4. S.K. Swan and M.J. Hursting, The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction, Pharmacotherapy, 20, 318-329 (2000). https://doi.org/10.1592/phco.20.4.318.34881
  5. S. Ahmad, A. Ahsan, M. George, O. Iqbal, W.P. Jeske, R. McKenna, B.E. Lewis, J.M. Walenga and J. Fareed, Simultaneous monitoring of argatroban and its major metabolite using an HPLC method: potential clinical applications, Clin. Appl. Thromb. Hemost., 5, 252-258 (1999). https://doi.org/10.1177/107602969900500409
  6. R. Stenz and K.H. Bauer, A new physiologically approached in vitro test for quick evaluation of the hemolytic activity of surfactants, Pharmazie, 51, 283-287 (1996).
  7. W.J. Husa and J.R. Adams, Isotonic solutions. II. The permeability of red corpuscles to various substances, J. Am. Pharm. Assoc. Sci. Ed., 33, 329 (1944). https://doi.org/10.1002/jps.3030331002
  8. K.W. Reed and S.H. Yalkowsky, Lysis of human red blood cells in the presence of various cosolvents, J. Parenter. Sci. Technol., 39, 64-69 (1985).
  9. F. Mottu, A. Laurent, D.A. Rufenacht and E. Doelker, Organic solvents for pharmaceutical parenterals and embolic liquids, PDA J. Pharm. Sci. Technol., 54, 456-469 (2000).
  10. J. Hauptmann, Pharmacokinetics of an emerging new class of anticoagulant/antithrombotic drugs. A review of small-molecule thrombin inhibitors, Eur. J. Clin. Pharmacol., 57, 751-758 (2002).
  11. S. Ahmad, L.H. Yang, A. Ahsan, K. Fu, O. Iqbal, D.A. Hoppensteadt, B.E. Lewis, J.M. Walenga and J. Fareed, Pharmacokinetics of argatroban in primates: evidence on endogenous uptake, Int. Angiol.. 19, 126-34 (2000).
  12. C.N. Berry, C. Lunven, C. Lecoffre, P. Lainee, S.E. O'Connor, F. Andre, B. Roger, D. Garrigou-Gadenne, A. Rouchouse, N.O. Roome and N. Vivan, Anticoagulant activity and pharmacokinetic properties of a sub-cutaneously administered mixed micellar formulation of argatroban in experimental animals, Thromb. Haemost., 84, 278-285 (2000).
  13. N. Duval, C. Lunven, D.P. O'Brien, A. Grosset, S.E. O'Connor and C.N. Berry, Antithrombotic actions of the thrombin inhibitor, argatroban, in a canine model of coronary cyclic flow: comparison with heparin, Br. J. Pharmacol., 118, 727-733 (1996). https://doi.org/10.1111/j.1476-5381.1996.tb15460.x
  14. W. Jeske, J.M. Walenga, B.E. Lewis and J. Fareed, Pharmacology of argatroban, Expert Opin. Invest. Drugs, 8, 625-654 (1999). https://doi.org/10.1517/13543784.8.5.625
  15. D. Callas and J. Fareed, Comparative pharmacology of site directed antithrombin agents. Implication in drug development, Thromb. Haemost., 74, 473-481 (1995).
  16. R. Nagashima, R.A. O'Reilly and G. Levy, Kinetics of pharmacologic effects in man: the anticoagulant action of warfarin, Clin. Pharmacol. Ther., 10, 22-35 (1969). https://doi.org/10.1002/cpt196910122