The Influence of Haemostatic System Maturation on the Dose-Response Relationship of Unfractionated Heparin
Abdallah Derbalah1, Stephen Duffull2, Katie Moynihan3,4,5,6
1School of Pharmacy, University of Otago, 18 Frederick St, North Dunedin, Dunedin, 9016, New Zealand. abdallah.derbalah@postgrad.otago.ac.nz.
Insights
Developing a new model for unfractionated heparin (UFH) in children improves dosing accuracy. This quantitative systems pharmacology model accounts for maturation, enhancing predictions of UFH
Area of Science:
- Pharmacology
- Pediatric Medicine
- Systems Biology
Background:
- Current unfractionated heparin (UFH) dosing for children relies on adult data, which is suboptimal due to differences in hemostatic maturation and drug handling.
- Pediatric hemostasis is immature and differs significantly from adult hemostasis, impacting drug response.
Purpose of the Study:
- To investigate how hemostatic system maturation affects the unfractionated heparin (UFH) dose-response relationship in children.
- To develop a predictive model for UFH pharmacokinetics and pharmacodynamics in pediatric patients.
Main Methods:
- Adapted an adult quantitative model for hemostasis to incorporate maturation of UFH pharmacokinetic (PK) parameters and age-related changes in coagulation factors.
- Predicted anti-factor Xa activity (aXa) and activated partial thromboplastin time (aPTT) using adult and adapted models.
- Compared model predictions with observed aXa and aPTT data from 31 pediatric patients undergoing extracorporeal membrane oxygenation (ECMO).
Main Results:
- The model incorporating maturation of both UFH PK and the hemostatic system demonstrated superior predictive performance for aXa and aPTT compared to models with only PK maturation or the original adult model.
- Hemostatic system maturation had a minor impact on baseline aPTT but significantly altered the time course of aPTT sensitivity to UFH.
- Variability in clotting factor concentrations, both between and within subjects, appears to be a major contributor to the variability in aPTT response to UFH.
Conclusions:
- Developed the first quantitative systems pharmacology (QSP) model linking physiological and pharmacological maturation to UFH effects and biomarkers in children.
- The model provides a mechanistic basis for understanding UFH response in pediatric patients.
- Clinical validation of this model could lead to the development of pediatric-specific, individualized UFH dosing recommendations.
Background:
Unfractionated heparin (UFH) dosing and monitoring guidelines for children are often extrapolated from adult data. This practice is suboptimal given the inherent differences in haemostatic maturation and drug handling in children compared with adults.
Objective:
The aim of this work was to investigate the impact of haemostatic system maturation on the dose-response relationship of UFH in children.
Methods:
A quantitative model for haemostasis in adults was adapted to account for maturation in UFH pharmacokinetic (PK) parameters with and without age-related changes in coagulation factor concentrations. The adult and adapted models were used to predict the time courses of anti-factor Xa activity (aXa) and activated partial thromboplastin time (aPTT) in patients receiving UFH infusion. Predictions from both models were compared with observed aXa and aPTT measurements from 31 paediatric patients receiving UFH during extracorporeal membrane oxygenation (ECMO).
Results:
The model with maturation for both UFH PK and the haemostatic system had an improved aXa and aPTT predictive performance compared with maturation in UFH PK only and the original adult model. Despite the minor effect of haemostatic system maturation on baseline aPTT, it led to substantial changes in the time course of aPTT sensitivity to UFH. This finding suggests that between-subject variability in clotting factors concentrations is potentially a major contributor to the overall variability of aPTT response to UFH. In addition, time-varying clotting factors concentrations may explain within-subject changes in aPTT sensitivity to UFH.
Conclusion:
We developed the first quantitative systems pharmacology (QSP) model that provides a mechanistic and quantitative basis for linking physiological and pharmacological maturation to UFH effect and response biomarkers. After appropriate clinical validation, the model could be useful for the development of paediatric-specific individualised UFH dosing recommendations.
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