Hesham S Al-Sallami (1), Fiona Newall (2,3,5), Paul Monagle (2,3,5), Vera Ignjatovic (2,3), Noel Cranswick (2,4), Stephen Duffull (1)
(1) School of Pharmacy, University of Otago, Dunedin, New Zealand (2) Department of Paediatrics, University of Melbourne, Australia (3) Murdoch Children’s Research Institute, Melbourne, Australia (4) Department of Pharmacology, University of Melbourne, Melbourne, Australia (5) Clinical Haematology, Royal Children’s Hospital, Melbourne Australia
Objectives: Unfractionated heparin (UFH) is the anticoagulant of choice in paediatric patients undergoing a variety of cardiac procedures. The ability to predict the dose-response relationship of UFH is essential in order to optimise its dosage. There are currently no population pharmacokinetic-pharmacodynamic (PKPD) models for UFH in paediatrics. The objectives of this work are to develop and evaluate a PKPD model to predict the dose-response relationship of UFH in paediatrics. Also, to explore the use of fat-free mass (FFM) to guide dose-individualisation of UFH in this population.
Methods: Data from 64 infants and children who received 75-100 IU/kg of UFH during cardiac angiography were analysed. Four plasma samples were collected at baseline and at 15, 30, 45, and 120 minutes post-dose. UFH concentration (231 measurements) was quantified using a protamine titration assay. UFH effect (164 measurements) was quantified using activated partial thromboplastin time (aPTT). A PKPD model was fitted to the data using the non-linear mixed effects modelling software NONMEM v7.2. Various patient covariates such as age, weight (Wt), and FFM were tested. The final model was evaluated using the likelihood ratio test and visual predictive checks (VPCs).
Results: A one-compartment model with linear elimination provided the best fit for the dose-concentration data. Wt and FFM had substantial influence on model fit; FFM was preferred statistically. A linear model provided the best fit for the concentration-effect data using the PPP&D sequential estimation method. Censored PD data (above the upper limit of quantification) were accounted for using the M3 method. The PKPD model performed well using visual predictive checks.
Conclusions: A PKPD model to describe the time-course of UFH effect was developed in a paediatric population which received a high single prophylactic bolus dose. FFM was shown to describe drug disposition well and can potentially be used in dose calculation after appropriate evaluation.
Reference: PAGE 24 (2015) Abstr 3448 [www.page-meeting.org/?abstract=3448]
Poster: Drug/Disease modeling - Paediatrics