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

溶解度 药品 亲脂性 化学 卵磷脂 多元分析 增溶 色谱法 医学 内科学 药理学 生物化学 有机化学
作者
Mariana Guimarães,Anil Maharaj,Andrea N. Edginton,Maria Vertzoni,Nikoletta Fotaki
出处
期刊:Pharmaceutics [Multidisciplinary Digital Publishing Institute]
卷期号:14 (2): 356-356
标识
DOI:10.3390/pharmaceutics14020356
摘要

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.
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