A Physiologically-Based Pharmacokinetic Framework for Prediction of Drug Exposure in Malnourished Children.

Erik Sjögren,Joel Tarning,E Niclas Jonsson,Karen I Barnes

doi:10.3390/pharmaceutics13020204

Abstract

Malnutrition in children is a global health problem, particularly in developing countries. The effects of an insufficient supply of nutrients on body composition and physiological functions may have implications for drug disposition and ultimately affect the clinical outcome in this vulnerable population. Physiologically-based pharmacokinetic (PBPK) modeling can be used to predict the effect of malnutrition as it links physiological changes to pharmacokinetic (PK) consequences. However, the absence of detailed information on body composition and the limited availability of controlled clinical trials in malnourished children complicates the establishment and evaluation of a generic PBPK model in this population. In this manuscript we describe the creation of physiologically-based bridge to a malnourished pediatric population, by combining information on (a) the differences in body composition between healthy and malnourished adults and (b) the differences in physiology between healthy adults and children. Model performance was confirmed using clinical reference data. This study presents a physiologically-based translational framework for prediction of drug disposition in malnourished children. The model is readily applicable for dose recommendation strategies to address the urgent medicinal needs of this vulnerable population.

Highlights

Malnutrition, as in undernutrition, is a major public-health problem throughout the developing world and is an underlying factor in over 50% of the 10–11 million children under 5 years of age who die of preventable causes each year [1]
This study presents the development and evaluation of a physiologically-based framework for prospective simulations of drug exposure in malnourished children; this framework is informed by previous knowledge on physiology of non-malnourished children and physiological consequences of malnutrition
The largest relative change in physiology due to malnutrition was predicted to occur for plasma protein levels (PSP = 0.494), followed by organ and tissue volume of spleen (PSP = 0.612) and fat (PSP = 0.624)

Summary

Introduction

Malnutrition, as in undernutrition, is a major public-health problem throughout the developing world and is an underlying factor in over 50% of the 10–11 million children under 5 years of age who die of preventable causes each year [1]. Different malnutrition classifications have been adopted and the most commonly used terms are stunting and wasting [2]. Stunting is defined by a low height-for-age (HFA) and is related to adverse health and development effects, which are largely irreversible. Different systems and ranges for the classification of malnutrition have been adopted over the decades; among these systems, the prevalence ranges to classify levels of wasting and stunting for children below 5 years have recently been revisited [3].

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