Similarities and Differences in Gastrointestinal Physiology Between Neonates and Adults: a Physiologically Based Pharmacokinetic Modeling Perspective

Abstract

Abstract. Physiologically based pharmacokinetic (PBPK) modeling holds great promise for anticipating the quantitative changes of pharmacokinetics in pediatric populations relative to adults, which has served as a useful tool in regulatory reviews. Although the availability of specialized software for PBPK modeling has facilitated the widespread applications of this approach in regulatory submissions, challenges in the implementation and interpretation of pediatric PBPK models remain great, for which controversies and knowledge gaps remain regarding neonatal development of the gastrointestinal tract. The commentary highlights the similarities and differences in the gastrointestinal pH and transit time between neonates and adults from a PBPK modeling prospective. Understanding the similarities and differences in these physiological parameters governing oral absorption would promote good practice in the use of pediatric PBPK modeling to assess oral exposure and pharmacokinetics in neonates.KEY WORDS: gastric emptying; gastrointestinal pH; neonates; physiologically based pharmacokinetic modeling; small intestinal transit time.Although physiologically based pharmacokinetic (PBPK) modeling holds great promise for facilitating pediatric drug development and regulatory review, the implementation and interpretation of pediatric PBPK models continues to face challenges, in which controversies and knowledge gaps remain regarding neonatal development of the gastrointestinal tract. In this context, we would like to offer some comments on the recent article of Khalil and Läer (1). In the work by Khalil and Läer (1), inaccurate predictions of oral pharmacokinetics of sotalol, using two PBPK models, were observed in neonates. The authors ascribed the poor predictions to factors related to the absorption rather than elimination or distribution processes and highlighted the lack of many age-specific physiological alterations in the parameterization of the used pediatric absorption models. Apart from the ontogeny of intestinal transporters and drugmetabolizing enzymes, the authors argued that gastrointestinal pH profiles and transit time should be considered as agerelated physiological variables to improve the predictive power of pediatric PBPK models. In this commentary, we provide additional information to facilitate a better understanding of the similarities and differences in gastrointestinal physiology between neonates and adults, which are of critical importance when using PBPK models to simulate oral pharmacokinetics in neonates.Despite the neutral pH in newborn stomach at delivery has been well recognized (2,3), much of the literature is replete with contradictory information on the maturation of gastric pH during the neonatal period. Some suggested that the neonatal gastric pH is greater than 5, which is quite different from the adult level (4-6); but others believed that the gastric pH of neonates stays within a more acidic range of 2-3, which is similar to that of adults (7,8). Upon careful examination of the reported n...

Utilizing Pediatric Physiologically Based Pharmacokinetic Models to Examine Factors That Contribute to Methadone Pharmacokinetic Variability in Neonatal Abstinence Syndrome Patients

“…In the current study, neonates were administered a standard diet. According to Yu et al, neonates administered a total diet (standard caloric intake) have a gastric emptying time comparable to adults. In addition, the transit time of the small intestine is also comparable to adults and is incorporated in the Simcyp Pediatric platform .…”

Developmental Changes in Pharmacokinetics and Pharmacodynamics

“…Available literature presents information that varies from a neutral gastric pH 1-3 days after birth followed by a progressive decrease over several weeks to years to reach adult values 12 and an acidic gastric pH soon after birth that persists even in the most preterm neonates. 13 Thus, there remains no clear consensus about the ontogeny of gastric acid production (rate and amount) and secretion or on its impact on drug absorption in the preterm/fullterm infant and during infancy. Perhaps the fact that preterm infants receive virtually continuous oral feeds containing acid-buffering milk might result in higher pH values than those seen in more mature infants.…”

Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition

“…Because such DDIs are mediated via the physiological environment of the gastrointestinal tract, such as gastrointestinal pH (Zhang et al 2014), the results can reasonably extrapolate to CYP2D6 PM subjects as well. Additionally, in view of the similarities in gastric and small intestinal pH between school-age children and adults from a developmental perspective (Yu et al 2014a), the recommendations are also suitable for the intended pediatric population.…”