1521-009X/44/7/1080–1089$25.00 http://dx.doi.org/10.1124/dmd.115.068700 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 44:1080–1089, July 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Special Section on Pediatric Drug Disposition and Pharmacokinetics Examining Small Intestinal Transit Time as a Function of Age: Is There Evidence to Support Age-Dependent Differences among Children? s Anil R. Maharaj and Andrea N. Edginton School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada Received December 7, 2015; accepted March 10, 2016 ABSTRACT The small intestine represents the region where the majority of drug and nutrient absorption transpires. Among adults, small intestinal transit kinetics is well delineated; however, the applicability of these values toward children remains unclear. This article serves to examine the relationship between age and mean small intestinal transit time (SITT) based on the available literature. In addition, the influence of alterations in intestinal transit time was explored among children using a model-based approach. Primary literature sources depicting SITT from children to adults were ascertained via the PubMed database. Data were limited to subjects without pathologies that could influence intestinal motility. Random-effect meta-regression models with between-study variability were employed to assess the influence of age on SITT. Three separate models with age as a linear or higher-order (i.e., second- and third-order polynomial) regressor were implemented to assess for the potential of both linear and curvilinear relationships. Examination of the influence of altered intestinal transit kinetics on the absorption of a sustained release theophylline preparation was explored among children between 8 and 14 years using physiologically based pharmacokinetic (PBPK) modeling. Age was not found to be a significant modulator of small intestinal transit within either the linear or higher-order polynomial meta-regression models. PBPK simulations indicated a lack of influence of variations in SITT on the absorption of theophylline from the examined sustained release formulation in older children. Based on the current literature, there is no evidence to suggest that mean SITT differs between children and adults. Introduction Estimation of bioavailability following oral compound administra- tion is an inherently complex procedure, requiring a fundamental understanding of the interplay between compound and formulation properties and the dynamic nature of the alimentary canal. Within the gastrointestinal (GI) tract a multitude of physiologic parameters can exert an influence on both the rate and extent of compound absorption, including gastric emptying time, small intestinal transit time (SITT), regional differences in pH and permeability, relative abundances of intestinal transporters and enzymes, and GI fluid volumes. Since developmental changes in any of the aforementioned parameters may impart differences in oral absorption between children and adults, there is an inherent need to identify which parameters change as a function of age and by how much. The small intestine is of particular importance because it represents the region where the majority of nutrient and xenobiotic absorption transpires (Lin et al., 1999). This is due to the presence of several morphologic features on the luminal surface, such as folds (valves of Kerckring), villi, and microvilli, which serve to significantly expand the absorptive surface area (Wilson, 1967). Correspondingly, knowledge of the time a xenobiotic spends traversing the small intestine is essential toward fostering predictions of oral compound absorption. This is particularly true for poorly absorbed compounds, where the extent of absorption is highly mediated by the time of contact between the compound and the small intestinal epithelium (Burton et al., 2002). Conceptually, the widely used maximum absorbable dose equation as proposed by Johnson and Swindell (1996) offers a simplistic overview of how SITT can influence the extent of compound absorption. Equation (1) utilizes the absorption rate constant (k a ), compound specific saturation solubility (C s ), small intestinal water volume (SIWV), and SITT to garner estimates of the maximum absorbable dose (MAD) following oral compound administration. MAD ¼ k a  C s  SIWV  SITT ð1Þ Based on eq. 1, shorter SITT (i.e., ↓SITT) would translate to lower compound availability following oral administration; whereas, longer SITT (i.e., ↑SITT) would result in the opposite. Owing to the influence of intestinal transit on oral drug disposition, there exists an inherent need to identify specific subpopulations exhibiting differences in SITT (Levy et al., 1972). In humans, estimates of SITT have been determined using a variety of techniques including lactulose hydrogen (H 2 ) breath tests, scintigraphy This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC). dx.doi.org/10.1124/dmd.115.068700. s This article has supplemental material available at dmd.aspetjournals.org. ABBREVIATIONS: GI, gastrointestinal; H 2 , hydrogen; LITT, large intestinal transit time; OCTT, orocecal transit time; PBPK, physiologically based pharmacokinetic; PK, pharmacokinetic; SITT, small intestinal transit time; SR, sustained release. 1080 at ASPET Journals on May 28, 2020 dmd.aspetjournals.org Downloaded from