Dose-finding and pharmacokinetics of therapeutic doses of tinzaparin in pediatric patients with thromboembolic events

Summary

In children, there is an increasing off-label use of low molecular weight heparin (LMWH). However, there is an absence of information on dosing and pharmacokinetics of LMWH over all age groups. The objectives of the current study were to determine i) the once daily dose required to achieve anti-Xa levels of 0.5–1.0 IU/mL, ii) the pharmacokinetics and iii) preliminary safety data using tinzaparin. The study took the form of a single centre open-label Phase II study performed in 35 children requiring anticoagulation for treatment of thromboembolism. Age groups studied were: 0-<2 months; 2 months-<1 year; 1-<5 years; 5-<10 years; 10–16 years. Both population pharmacokinetic analysis using nonlinear mixed-effect modeling techniques and model-independent pharmacokinetic methods were employed. Results showed a relationship of age and dose requirements, clearance, time to peak anti-Xa level and volume of distribution. Younger children required an increased dose, cleared tinzaparin more rapidly, had anti-Xa levels peak earlier and had an increased volume of distribution. Younger children were more likely to be below target range than older children, with up to 75% of children <1 year being below the target anti-Xa level. Four recurrences and one major bleed occurred. In conclusion, there is an inverse relationship of age on dose requirements related to volume of distribution, clearance and time to peak anti- Xa. Children <5 years likely require dose adjustment samples to be drawn 2–3 hours post injection. Infants require anti-Xa levels to be monitored at least twice monthly.

Keywords

Low molecular weight heparin - treatment - pediatrics - dosages - Pharmacokinetics

• References

• 1 Andrew M, David M, Adams M. et al Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood 1994; 83: 1251-7.
• 2 Schmidt B, Andrew M. Neonatal thrombosis: report of a prospective Canadian and international registry. Pediatrics 1995; 96: 939-43.
• 3 van Ommen CH, Heijboer H, Buller HR. et al Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands. J Pediatr 2001; 139: 676-81.
• 4 Andrew M, Marzinotto V, Massicotte P. et al Heparin therapy in pediatric patients: a prospective cohort study. Pediatr Res 1994; 35: 78-83.
• 5 Streif W, Andrew M, Marzinotto V. et al Analysis of warfarin therapy in pediatric patients: A prospective cohort study of 319 patients. Blood 1999; 94: 3007-14.
• 6 Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337: 688-98.
• 7 Massicotte P, Adams M, Marzinotto V. et al Lowmolecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study. J Pediatr 1996; 128: 313-8.
• 8 Nohe N, Flemmer A, Rumler R. et al The low molecular weight heparin dalteparin for prophylaxis and therapy of thrombosis in childhood: a report on 48 cases. Eur J Pediatr 1999; 158 (Suppl. 03) S134-9.
• 9 Punzalan RC, Hillery CA, Montgomery RR. et al Low-molecular-weight heparin in thrombotic disease in children and adolescents. J Pediatr Hematol Oncol 2000; 22: 137-42.
• 10 Dix D, Andrew M, Marzinotto V. et al The use of low molecular weight heparin in pediatric patients: a prospective cohort study. J Pediatr 2000; 136: 439-45.
• 11 Laporte S, Mismetti P, Piquet P. et al Population pharmacokinetic of nadroparin calcium (Fraxiparine) in children hospitalised for open heart surgery. Eur J Pharm Sci 1999; 8: 119-25.
• 12 Hull RD, Raskob GE, Pineo GF. et al Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximalvein thrombosis. N Engl J Med 1992; 326: 975-82.
• 13 Simonneau G, Sors H, Charbonnier B. et al A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l’Embolie Pulmonaire. N Engl J Med 1997; 337: 663-9.
• 14 Monagle P, Michelson AD, Bovill E. et al Antithrombotic therapy in children. Chest 2001; 119: 344S-370S.
• 15 Gibaldi M, Perrier D. Pharmacokinetics. NewYork: Marcel Dekker Inc.; 1982
• 16 Massicotte P, Julian JA, Marzinotto V. et al Dosefinding and pharmacokinetic profiles of prophylactic doses of a low molecular weight heparin (reviparin-sodium) in pediatric patients. Thromb Res 2003; 109: 93-9.
• 17 Monagle P, Chan A, Massicotte P. et al Antithrombotic therapy in children: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 645S-87S.
• 18 Kuhle S, Mitchell L, Massicotte P. et al Hemostatic disorders of the newborn. In: Taeusch HW, Ballard RA, Gleason CA. editors. Avery’s Diseases of the Newborn. Philadelphia: Saunders; 2004: 1145-79.
• 19 Andrew M, Vegh P, Johnston M. et al Maturation of the hemostatic system during childhood. Blood 1992; 80: 1998-2005.
• 20 Streif W, Goebel G, Chan AK. et al Use of low molecular mass heparin (enoxaparin) in newborn infants: a prospective cohort study of 62 patients. Arch Dis Child Fetal Neonatal Ed 2003; 88: F365-70.
• 21 Massicotte P, Julian JA, Gent M. et al An open-label randomized controlled trial of low molecular weight heparin compared to heparin and coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial. Thromb Res 2003; 109: 85-92.
• 22 Levine MN, Raskob G, Landefeld S. et al Hemorrhagic complications of anticoagulant treatment. Chest 1998; 114: 511S-523S.
• 23 Prandoni P, Siragusa S, Girolami B. et al The incidence of heparin-induced thrombocytopenia in medical patients treated with low molecular weight heparin. Blood 2005; 0: 200503091
• 24 Christiansen HM, Lassen MR, Borris LC. et al Biologic tolerance of two different low molecular weight heparins. Semin Thromb Hemost 1991; 17: 450-4.
• 25 Vieira A, Berry L, Ofosu F. et al Heparin sensitivity and resistance in the neonate: an explanation. Thromb Res 1991; 63: 85-98.
• 26 Kuhle S, Massicotte MP, Andrew M. et al Ex-vivo thrombin generation capacity in pediatric patients receiving tinzaparin. J Thromb Haemost 2003; 1: OC421.