Abstract 19468: Physiology Based Modeling to Support Pediatric Cardiovascular Drug Research — Potential Applications Using Amiodarone and Enalapril as Examples
Background: Recently failed clinical investigations in children highlight the difficulty of bridging adult and pediatric pharmacotherapy. We suggest that the methodology of physiology based modeling is a scientific tool which might help to bridge these populations. The important and commonly used drugs enalapril and amiodarone serve as examples for an approach focusing on pharmacokinetics and pharmacodynamics.
Methods: For enalapril and amiodarone physiology based models for adults were developed using the PK-SIM® software and compared to adult data. The models encompassed intravenous amiodarone and oral enalapril application as well as conversion to its active metabolite enalaprilate. For enalapril the pharmacodynamic model of the renin angiotensin-aldosterone cascade was built to be able to predict the effect on the biomarkers angiotensin one and two. For amiodarone a clearance scaling step was already conducted to grasp growth and enzyme maturation from child- to adulthood including the enzyme CYP3A4. Simulations were compared to pediatric trial data and used to evaluate an actual clinical case of a newborn treated with the drug.
Results: The enalapril model is able to describe plasma concentrations and urinary excretion data of enalapril and enalaprilate from various trials adequately and their effect on angiotensin one and two. For amiodarone the measured steady state concentrations from the adult study were comparable with the simulated concentrations. The clearance of amiodarone in children changed over time, reaching maximum values at 1–4 years before declining to adult values. Data from a trial using intravenous amiodarone in children were adequately described by the model and the plasma concentrations the newborn simulated underlining the need for consequent amiodarone loading.
Conclusions: We were able to develop models for adult and pediatric application of amiodarone and adult application of enalapril using physiology based modeling. We hypothesize that harnessing this technique more widespread in pediatric pharmacotherapy it can be used to a) construct age adapted dosing regimens b) predict the effect on drug biomarkers optimizing the chance for overall trial success and individual patient care.
- © 2010 by American Heart Association, Inc.