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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
1   Stollery Children’s Hospital, Edmonton, Alberta, Canada
,
Patti Massicotte
1   Stollery Children’s Hospital, Edmonton, Alberta, Canada
2   Division of Haematology and Oncology, Hospital for Sick Children, Toronto, Ontario, Canada
,
Maria Dinyari
3   Population Health Sciences, Hospital for Sick Children, Toronto, Ontario, Canada
,
Patsy Vegh
3   Population Health Sciences, Hospital for Sick Children, Toronto, Ontario, Canada
,
Debra Mitchell
4   LEO Pharma Inc., Thornhill, Ontario, Canada
,
Velma Marzinotto
3   Population Health Sciences, Hospital for Sick Children, Toronto, Ontario, Canada
,
Antony Chan
5   Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
,
Hank Pieniaszek
6   HPP Consulting and Services Inc, Darlington, Maryland, USA
,
Lesley G. Mitchell
1   Stollery Children’s Hospital, Edmonton, Alberta, Canada
3   Population Health Sciences, Hospital for Sick Children, Toronto, Ontario, Canada
› Author AffiliationsGrant support: Stefan Kuhle was supported by a grant from the Austrian Science Fund (FWF), Project # J-2038. Lesley Mitchell is a scholar of the Canadian Institutes of Health Research. The work was supported by a joint grant DOP-51711 from the Canadian Institute of Health Research and Leo Pharma Inc, Thornhill, Canada.
Further Information

Publication History

Received 30 March 2005

Accepted after revision 29 September 2005

Publication Date:
07 December 2017 (online)

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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
 

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