Hesham Al-Sallami, Fiona Newall, Paul Monagle, Vera Ignjatovic, Noel Cranswick, Stephen Duffull

Unfractionated heparin (UFH) is the anticoagulant of choice in paediatric patients undergoing a variety of cardiac procedures. There are currently no population pharmacokinetic-pharmacodynamic (PKPD) models for UFH in paediatrics. To develop and evaluate a PKPD model of UFH in paediatrics. Data from 64 children who received 75-100 IU/kg of UFH during cardiac angiography were analysed. Five blood samples were collected at baseline and at 15, 30, 45, and 120 minutes post-dose. UFH concentration was quantified using a protamine titration assay. UFH effect was quantified using activated partial thromboplastin time (aPTT). A PKPD model was fitted using the non-linear mixed effects modelling. Patient covariates such as sex, weight (WT), and fat-free mass (FFM) were tested. The final model was evaluated using the likelihood ratio test and visual predictive checks (VPCs). A one compartment model with linear elimination provided the best fit for the dose-concentration data. FFM was a significant covariate on clearance. A linear model provided the best fit for the concentration-effect data using aPTT as a biomarker for effect. The models performed well using VPCs. However, when used to simulate UFH infusion (at a much lower dose), the model overpredicted target aPTT responses. A PKPD model to describe the time-course of UFH effect was developed in a paediatric population. FFM was shown to describe drug disposition well. However, when applied to smaller UFH infusion doses, the model overpredicts target aPTT responses. This unsuccessful extrapolation may be attributed to a possible non-linear relationship of heparin PKPD.