Oral drug absorption in pediatrics: the intestinal wall, its developmental changes and current tools for predictions

Abstract

The dissolution, intestinal absorption and presystemic metabolism of a drug depend on its physicochemical characteristics but also on numerous physiological (e.g. gastrointestinal pH, volume, transit time, morphology) and biochemical factors (e.g. luminal enzymes and flora, intestinal wall enzymes and transporters). Over the past decade, evidence has accumulated indicating that these factors may differ in children and adults resulting in age-related changes in drug exposure and drug response. Thus, drug dosage may require adjustment for the pediatric population to ensure the desired therapeutic outcome and to avoid side-effects. Although tremendous progress has been made in understanding the effects of age on intestinal physiology and function, significant knowledge gaps remain. Studying and predicting pharmacokinetics in pediatric patients remains challenging due to ethical concerns associated with clinical trials in this vulnerable population, and because of the paucity of predictive in vitro and in vivo animal assays. This review details the current knowledge related to developmental changes determining intestinal drug absorption and pre-systemic metabolism. Supporting experimental approaches as well as physiologically based pharmacokinetic modeling are also discussed together with their limitations and challenges. Copyright © 2016 John Wiley & Sons, Ltd.

Keywords: intestinal absorption; ontogeny; pediatrics; physiologically based pharmacokinetic modeling.

Figure 1

Age‐related changes in gastric pH under fasting conditions. Error bars indicate pH range (solid symbols) or standard deviation associated with mean pH (open symbols). References: ▼ 203, ● 204, ♦ 205, ■ 206, ▲ 207, ○ 208, □ 209, ◊ 25 (this latter reference reports pH data for subjects aged 2 months to 18 years)

Figure 2

Excretion of digoxin reduced metabolites at different ages. Digitalized children and adults were examined for metabolites recovered in urine samples. Subjects were classified as excretors when digoxin reduced metabolites accounted for at least 5% of the total drug‐related material. Adapted from 79

Figure 3

Age‐related changes in human intestinal CYP3A4 activity as measured by the rate of testosterone 6‐ß hydroxylation. Sample size given by the numbers in brackets.Reproduced from 88

Figure 4

Age‐related changes in busulfan plasma exposure of after oral dosing. C _max values were normalized for the dose and body weight. Adapted from 101