Pharmacodynamic Considerations in the Selection of Dosage of Tinzaparin for Various Indications: Experimental Studies in Primates

Like unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs) are polypharmacologic agents that can modulate the hemostatic system at multiple points. Thus, to select an optimal dose of LMWH for a given indication, it is necessary to consider multiple actions of the drug. In this study, nonhuman primates were treated with intravenous or subcutaneous boluses of the LMWH tinzaparin or UFH. Doses were selected on the basis of the expected prophylactic (75 U/kg) and therapeutic (175 U/kg) dosing of tinzaparin. Blood samples were drawn periodically up to 24 hours after administration. Circulating anti-Xa and anti-thrombin (anti-IIa) activities determined using amidolytic assays were used to estimate plasma tinzaparin (heparin) concentrations. In addition, total tissue factor pathway inhibitor (TFPI) levels were measured in these primates. Subcutaneous administration of 75 U/kg tinzaparin resulted in plasma levels of ∼0.2 to 0.3 U/mL, concentrations sufficient for DVT prophylaxis. Such drug levels were not associated with a significant release of TFPI. Intravenous administration of the same dose resulted in a peak drug level of ∼1.5 anti-Xa U/mL. The elimination half-life was approximately 1 hour. Thus, intravenously administered tinzaparin may be useful for providing anticoagulation during coronary interventions. Subcutaneous administration of 175 U/kg resulted in tinzaparin levels of ∼0.7 anti-Xa U/mL and a significant increase in TFPI levels. Interestingly, the increase in TFPI levels occurred over a different time frame than anticoagulant activity. Intravenous administration of 175 U/kg resulted in peak drug concentrations of almost 5 anti-Xa U/mL. The pharmacokinetic behavior of intravenously administered tinzaparin was comparable to that of UFH. The data show that the pharmacokinetic and pharmacodynamic effects measured using different assays widely differ. For a proper pharmacodynamic analysis, multiple assays should be considered, given that both UFH and LMWHs are polycomponent in nature.

KEYWORDS

Heparin - unfractionated heparin (UFH) - low-molecular-weight heparin (LMWH) - tinzaparin - tissue factor pathway inhibitor (TFPI) - pharmacokinetics

REFERENCES

• 1 Fareed J, Jeske W, Hoppensteadt D, Clarizio R, Walenga J M. Are the available low-molecular-weight heparin preparations the same?.  Semin Thromb Hemost. 1996;  22(suppl 1) 77-91
• 2 Casu B, Torri G. Structural characterization of low molecular weight heparins.  Semin Thromb Hemost. 1999;  25(suppl 3) 17-25
• 3 Hirsh J, Warkentin T E, Shaughnessy S G et al.. Heparin and low molecular weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy and safety.  Chest. 2001;  119 64S-94S
• 4 Leclerc J R, Geerts W H, Desjardins L et al.. Prevention of venous thromboembolism after knee arthroplasty. A randomized, double-blind trial comparing enoxaparin with warfarin.  Ann Intern Med. 1996;  124 619-626
• 5 Bergqvist D, Benoni G, Bjorgell O et al.. Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement.  N Engl J Med. 1996;  335 696-700
• 6 Heit J A, Berkowitz S D, Bona R Ardeparin Arthroplasty Study Group et al.. Efficacy and safety of low molecular weight heparin (ardeparin sodium) compared to warfarin for the prevention of venous thromboembolism after total knee replacement surgery: a double-blind, dose-ranging study.  Thromb Haemost. 1997;  77 32-38
• 7 Koppenhagen K, Adolf J, Matthes M et al.. Low molecular weight heparin and prevention of postoperative thrombosis in abdominal surgery.  Thromb Haemost. 1992;  67 627-630
• 8 Hunt B J, Doughty H A, Majumdar G et al.. Thromboprophylaxis with low molecular weight heparin (fragmin) in high-risk pregnancies.  Thromb Haemost. 1997;  77 39-43
• 9 Fareed J, Callas D D, Hoppensteadt D, Jeske W, Walenga J M. Recent developments in antithrombotic agents.  Expert Opin Investig Drugs. 1995;  4 389-412
• 10 Godwin J. Use of low molecular weight heparins in malignancy-related thromboembolic disorders: a clinical review.  Clin Appl Thromb Hemost. 1996;  2(suppl 1) S28-S34
• 11 Marmur J D, Anand S X, Bagga R S et al.. The activated clotting time can be used to monitor the low molecular weight heparin dalteparin after intravenous administration.  J Am Coll Cardiol. 2003;  41 394-402
• 12 Rabah M M, Premmereur J, Graham M et al.. Usefulness of intravenous enoxaparin for percutaneous coronary intervention in stable angina pectoris.  Am J Cardiol. 1999;  84 1391-1395
• 13 Kereiakes D J, Grines C, Fry E. for the NICE 1 and NICE 4 Investigators . National investigators collaborating on enoxaparin.  J Invasive Cardiol. 2001;  13 272-278
• 14 Hoppensteadt D A, Jeske W, Fareed J, Bermes E W. The role of tissue factor pathway inhibitor in the mediation of the antithrombotic actions of heparin and low-molecular-weight heparin.  Blood Coagul Fibrinolysis. 1995;  6 S57-S64
• 15 Jeske W, Hoppensteadt D, Klauser R et al.. Effect of repeated aprosulate and enoxaparin administration on TFPI antigen levels.  Blood Coagul Fibrinolysis. 1995;  6 119-124
• 16 Sandset P M, Abildgaard P, Larsen M L. Heparin induces release of extrinsic coagulation pathway inhibitor (EPI).  Thromb Res. 1988;  50 803-813
• 17 Alban S. Molecular weight-dependent influence of heparin on the form of tissue factor pathway inhibitor circulating in plasma.  Semin Thromb Hemost. 2001;  27 503-511
• 18 Antman E M, McCabe C H, Marble S J et al.. Dose ranging trial of enoxaparin for unstable angina: results of TIMI 11A.  Circulation. 1996;  94 I-554 , (abst)
• 19 Fragmin during Instability in Coronary Artery Disease (FRISC) Study Group . Low-molecular-weight heparin during instability in coronary artery disease.  Lancet. 1996;  347 561-568
• 20 Cohen M, Demers C, Gurfinkel E, Fromell E, Langer A, Turpie A GG. ESSENCE Group: primary end point analysis from the ESSENCE trial: enoxaparin vs unfractionated heparin in unstable angina and non-Q wave infarction.  Circulation. 1996;  94 I-554 , (abst)
• 21 Neely J L, Carlson S S, Lenhart S E. Tinzaparin sodium: a low-molecular-weight heparin.  Am J Health Syst Pharm. 2002;  59 1426-1436
• 22 Samama M M, Gerotziafas G T. Comparative pharmacokinetics of LMWHs.  Semin Thromb Hemost. 2000;  26(suppl 1) 31-38
• 23 Iqbal O, Jeske W, Bacher P, Hoppensteadt D A, Walenga J M, Fareed F. A comparison of the pharmacokinetic and pharmacodynamic profiles of clexane and lovenox in dogs.  Semin Thromb Hemost. 1993;  19(suppl 1) 199-209
• 24 Atha D H, Lormeau J C, Petitou M, Rosenberg R D, Choay J. Contribution of 3-O- and 6-O-sulfated glucosamine residues in the heparin-induced conformational change in antithrombin III.  Biochemistry. 1987;  26 6454-6461
• 25 Laurent T C, Tengblad A, Thunberg L, Hook M, Lindahl U. The molecular weight dependence of the anticoagulant activity of heparin.  Biochem J. 1978;  175 691-701