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

Abstract

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.

Aspects of anticoagulation in children

“…Pharmacokinetic and pharmacodynamic responses to anticoagulants are also age-dependent (McDonald et al, 1981;Massicotte et al, 1996;Streif et al, 1999;Kuhle et al, 2005;Ignjatovic et al, 2006). Understanding the changing quantitative and qualitative aspects of haemostasis is crucial for those needing to risk stratify, diagnose and optimally manage thromboses in children.…”

“…Formal, adequately powered pharmacokinetic studies in children are scarce, yet essential, to guide age-based dosing. Paediatric dose recommendations for the use of enoxaparin, dalteparin, reviparin and tinzaparin are based on data from these studies (Massicotte et al, 1996(Massicotte et al, , 2003bNohe et al, 1999;Dix et al, 2000;Punzalan et al, 2000;Kuhle et al, 2005) (Table II). Younger children, especially those <2 months or <5 kg need higher doses than older children to achieve the same anti-FXa effect.…”

“…Younger children, especially those <2 months or <5 kg need higher doses than older children to achieve the same anti-FXa effect. This is generally attributed to a greater volume of distribution together with faster clearance and developmental haemostatic differences (Massicotte et al, 1996;Kuhle et al, 2005;Monagle et al, 2008).…”

“…Once daily dosing in children risks under treatment and, in addition, a potential bleeding risk if higher doses are given to allow a once daily regime (Massicotte, 2000). Tinzaparin is usually given once daily but a pharmacokinetic study showed that this may not be optimum in children because the median half life of anti-FXa activity was 3AE4-8AE8 h across the age groups and by 24 h there was virtually no anti-FXa nor anti-FIIa activity (Kuhle et al, 2005).…”

Prevention and Treatment of Thrombosis in Pediatric and Congenital Heart Disease

“…157 In addition, CVL-associated thrombosis may result in loss of vascular access important for lifesaving therapy in certain illnesses, including heart transplantation. 28,169,213 • Many children with CHD have persistent right-to-left intracardiac shunts with the potential for venous emboli to travel through the heart to the brain with resultant stroke. …”