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

Stefan Kuhle; Patti Massicotte; Maria Dinyari; Patsy Vegh; Debra Mitchell; Velma Marzinotto; Antony Chan; Hank Pieniaszek; Lesley G. Mitchell

doi:10.1160/TH05-03-0215

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 94(06): 1164-1171
DOI: 10.1160/TH05-03-0215

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

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

Stefan Kuhle

¹Stollery Children’s Hospital, Edmonton, Alberta, Canada

,

Patti Massicotte

¹Stollery Children’s Hospital, Edmonton, Alberta, Canada

²Division of Haematology and Oncology, Hospital for Sick Children, Toronto, Ontario, Canada

,

Maria Dinyari

³Population Health Sciences, Hospital for Sick Children, Toronto, Ontario, Canada

,

Patsy Vegh

³Population Health Sciences, Hospital for Sick Children, Toronto, Ontario, Canada

,

Debra Mitchell

⁴LEO Pharma Inc., Thornhill, Ontario, Canada

,

Velma Marzinotto

³Population Health Sciences, Hospital for Sick Children, Toronto, Ontario, Canada

,

Antony Chan

⁵Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada

,

Hank Pieniaszek

⁶HPP Consulting and Services Inc, Darlington, Maryland, USA

,

Lesley G. Mitchell

¹Stollery Children’s Hospital, Edmonton, Alberta, Canada

³Population Health Sciences, Hospital for Sick Children, Toronto, Ontario, Canada

› Author Affiliations

Abstract

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

Full Text

References

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