Understanding the Impact of Age-Related Changes in Pediatric GI Solubility by Multivariate Data Analysis.

Mariana Guimarães,Nikoletta Fotaki,Maria Vertzoni,Anil Maharaj,Andrea Edginton

doi:10.3390/pharmaceutics14020356

Abstract

The aim of this study was to understand drug solubilization as a function of age and identify drugs at risk of altered drug solubility in newborns and young infants in comparison to adults. Multivariate statistical analysis was used to understand drug solubilization as a function of drug’s physicochemical properties and the composition of gastrointestinal fluids. The solubility of seven poorly soluble compounds was assessed in adult and age-specific fasted and fed state biorelevant media. Partial least squares regression (PLS-R) was used to assess the influence of (i) drug physicochemical properties and (ii) age-related changes in simulated GI fluids, as well as (iii) their interactions, on the pediatrics-to-adult solubility ratio (Sp/Sa (%)). For five out of seven of the compounds investigated, Sp/Sa (%) values fell outside of the 80–125% limits in at least one of the pediatric media. Lipophilicity was responsible for driving drug solubility differences between adults and children in all the biorelevant media investigated, while drug ionization was most relevant in the fed gastric media, and the fasted/fed intestinal media. The concentration of bile salts and lecithin in the fasted and fed intestinal media was critical in influencing drug solubility, while food composition (i.e., cow’s milk formula vs. soy formula) was a critical parameter in the fed gastric state. Changes in GI fluid composition between younger pediatric patients and adults can significantly alter drug luminal solubility. The use of pediatric biorelevant media can be helpful to identify the risk of altered drug solubilization in younger patients during drug development.

Highlights

Oral drug performance is dependent on oral drug bioavailability, the rate and extent of the drug reaching the systemic circulation unchanged
Solubility results measured in each pediatric medium vs. solubility in adult medium are expressed as the ratio Sp/Sa (%) (Figures 2 and 3)
For the majority of the investigated compounds, drug solubility fell outside an 80–125% range from adult values in at least one of the developed pediatric media

Summary

Introduction

Oral drug performance is dependent on oral drug bioavailability, the rate and extent of the drug reaching the systemic circulation unchanged. GI absorption is influenced by multiple factors, such as the extent and rate of drug dissolution, the formation of drug insoluble complexes, drug decomposition, and regional changes in drug permeability [1]. The drug that is in solution will be absorbed, and the magnitude of dissolved drug concentrations in the lumen influences the rate and extent of drug absorption [1]. Drug solubility in GI fluids dictates the upper concentration limit. Both intrinsic (e.g., anatomical, physiological) and extrinsic (e.g., nutritional) age-related changes affect the composition of GI fluids, which will impact drug solubility in the GI tract of pediatric patients [2]. There is a high rate of change in these intrinsic and extrinsic factors in the youngest subpopulations, especially during the first months of life [2]

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