The Direct Thrombin Inhibitor Argatroban: A Review of Its Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Relationships

ABSTRACT

The direct thrombin inhibitor argatroban exhibits pharmacological properties that are distinctly different from those of other thrombin inhibitors. Within its clinically relevant dose range, argatroban shows linear pharmacokinetic behavior and concentrations that are well correlated with anticoagulant effects. The pharmacokinetic profile can be described by a two-compartment model with first-order elimination. Whereas argatroban does not require dosage modification in patients with renal dysfunction and has been demonstrated to be safe and well tolerated in hemodialysis, dosing precautions are recommended in hepatically impaired patients. The effects of high-dose or prevention therapy can be monitored by various coagulation parameters like activated clotting time (ACT), activated partial thromboplastin time (aPTT), or ecarin clotting time (ECT). Whereas the aPTT response to argatroban varies with aPTT reagent, ECT seems to be a more specific monitoring parameter for the direct thrombin inhibitor. Argatroban influences the prothrombin time, expressed as the international normalized ratio (INR), which complicates the transition to oral anticoagulation with coumarin derivatives. An overlap period with warfarin for a minimum of 4 to 5 days, aimed at an INR of > 4 on a Quick-type prothrombin time assay, is recommended before discontinuation of argatroban therapy. The good predictability of the anticoagulant effect of argatroban, together with its fast clearance and lack of influence by renal dysfunction, makes argatroban an ideal antithrombotic agent in the intensive care unit setting and in interventional cardiology.

KEYWORDS

Argatroban - pharmacokinetics - pharmacodynamics - monitoring

REFERENCES

• 1 Di Nisio M, Middeldorp S, Büller H R. Direct thrombin inhibitors.  N Engl J Med. 2005;  353 1028-1040
• 2 Yeh R W, Jang I K. Argatroban: update.  Am Heart J. 2006;  151 1131-1138
• 3 Fareed J, Jeske W P. Small-molecule direct antithrombins: argatroban.  Best Pract Res Clin Haematol. 2004;  17 127-138
• 4 Lewis B E, Hursting M J. Heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A 3rd ed. New York, NY; Marcel Dekker 2004: 437-474
• 5 Berry C N, Girardot C, Lecoffre C, Lunven C. Effects of the synthetic thrombin inhibitor argatroban on fibrin- or clot-incorporated thrombin: comparison with heparin and recombinant hirudin.  Thromb Haemost. 1994;  72 381-386
• 6 Ahmad S, Ahsan A, George M et al.. Simultaneous monitoring of argatroban and its major metabolite using an HPLC method: potential clinical applications.  Clin Appl Thromb Hemost. 1999;  5 252-258
• 7 http://www.fda.gov/CDER/consumerinfo/druginfo/argatrob.HTM (Summary of Medicinal Product Characteristics Argatroban [last access March 10, 2008])
• 8 Tran J Q, Di Cicco R A, Sheth S B et al.. Assessment of the potential pharmacokinetic and pharmacodynamic interactions between erythromycin and argatroban.  J Clin Pharmacol. 1999;  39 513-519
• 9 Brown P M, Hursting M J. Lack of pharmacokinetic interactions between argatroban and warfarin.  Am J Health Syst Pharm. 2002;  59 2078-2083
• 10 Inglis A M, Sheth S B, Hursting M J, Tenero D M, Graham A M, DiCicco R A. Investigation of the interaction between argatroban and acetaminophen, lidocaine, or digoxin.  Am J Health Syst Pharm. 2002;  59 1258-1266
• 11 Honisko M E, Fink J M, Militello M P et al.. Compatibility of argatroban with selected cardiovascular agents.  Am J Health System Pharm. 2004;  61 2415-2418
• 12 Swan S K, Peter J, Lambrecht L, Hursting M. Comparison of anticoagulant effects and safety of argatroban and heparin in healthy subjects.  Pharmacotherapy. 2000;  20 756-770
• 13 Cox D S, Kleiman N S, Boyle D A et al.. Pharmacokinetics and pharmacodynamics of argatroban in combination with a platelet glycoprotein IIB/IIIA receptor antagonist in patients undergoing percutaneous coronary intervention.  J Clin Pharmacol. 2004;  44 981-990
• 14 Swan S K, Hursting M J. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction.  Pharmacotherapy. 2000;  20 318-329
• 15 Murray P T, Reddy B V, Grossman E J et al.. A prospective comparison of three argatroban treatment regimens during hemodialysis in end-stage renal disease.  Kidney Int. 2004;  66 2446-2453
• 16 Levine R L, Hursting M J, McCollum D. Argatroban anticoagulation in heparin-induced thrombocytopenia with hepatic dysfunction.  Chest. 2006;  129 1167-1175
• 17 Harder S, Klinkhardt U, Alvarez J M. Avoidance of bleeding during surgery in patients receiving anticoagulant and/or antiplatelet therapy: pharmacokinetic and pharmacodynamic considerations.  Clin Pharmacokinet. 2004;  43 963-981
• 18 Hursting M J, Dubb J, Verme-Gibboney C N. Argatroban anticoagulation in pediatric patients: a literature analysis.  J Pediatr Hematol Oncol. 2006;  28 4-10
• 19 Harder S, Merz M, Klinkhardt U et al.. Influence of argatroban on coagulation parameters in heparin-induced thrombocytopenia patients after cardiothoracic surgery.  J Thromb Haemost. 2007;  9 1982-1984
• 20 Lewis B E, Matthai Jr W H, Cohen M, Moses J W, Hursting M J. Leya F and the ARG-216/310/311 Study Investigators. Argatroban anticoagulation during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia.  Catheter Cardiovasc Interv. 2002;  57(2) 177-184
• 21 Francis J L, Hursting M J. Effect of argatroban on the activated partial thromboplastin time: a comparison of 21 commercial reagents.  Blood Coagul Fibrinolysis. 2005;  16 251-257
• 22 Iqbal O, Ahmad S, Lewis B E, Walenga J M, Rangel Y, Fareed J. Monitoring of argatroban in ARG310 study: potential recommendations for its use in interventional cardiology.  Clin Appl Thromb Hemost. 2002;  8 217-224
• 23 Harder S, Graff J, Klinkhardt U et al.. Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effects on prothrombin time, activated partial thromboplastin time, and ecarin clotting time.  Thromb Haemost. 2004;  91 1137-1145
• 24 Hursting M J, Lewis B E, Macfarlane D E. Transitioning from argatroban to warfarin therapy in patients with heparin-induced thrombocytopenia.  Clin Appl Thromb Hemost. 2005;  11 279-287
• 25 Fenyvesi T, Jorg I, Harenberg J. Effect of phenprocoumon on monitoring of lepirudin, argatroban, melagatran and unfractionated heparin with the PiCT method.  Pathophysiol Haemost Thromb. 2002;  32 174-179
• 26 Warkentin T E, Greinacher A, Craven S, Dewar L, Sheppard J A, Ofosu F A. Differences in the clinically effective molar concentrations of four direct thrombin inhibitors explain their variable prothrombin time prolongation.  Thromb Haemost. 2005;  94 958-964