Evaluation of Physiologically Based Pharmacokinetic Models to Predict the Absorption of BCS Class I Drugs in Different Pediatric Age Groups

Abstract

Age‐related changes in many parameters affecting drug absorption remain poorly characterized. The objective of this study was to apply physiologically based pharmacokinetic (PBPK) models in pediatric patients to investigate the absorption and pharmacokinetics of 4 drugs belonging to the Biopharmaceutics Classification System (BCS) class I administered as oral liquid formulations. Pediatric PBPK models built with PK‐Sim/MoBi were used to predict the pharmacokinetics of acetaminophen, emtricitabine, theophylline, and zolpidem in different pediatric populations. The model performance for predicting drug absorption and pharmacokinetics was assessed by comparing the predicted absorption profile with the deconvoluted dose fraction absorbed over time and predicted with observed plasma concentration‐time profiles. Sensitivity analyses were performed to analyze the effects of changes in relevant input parameters on the model output. Overall, most pharmacokinetic parameters were predicted within a 2‐fold error range. The absorption profiles were generally reasonably predicted, but relatively large differences were observed for acetaminophen. Sensitivity analyses showed that the predicted absorption profile was most sensitive to changes in the gastric emptying time (GET) and the specific intestinal permeability. The drug's solubility played only a minor role. These findings confirm that gastric emptying time, more than intestinal permeability or solubility, is a key factor affecting BCS class I drug absorption in children. As gastric emptying time is prolonged in the fed state, a better understanding of the interplay between food intake and gastric emptying time in children is needed, especially in the very young in whom the (semi)fed condition is the prevailing prandial state, and hence prolonged gastric emptying time seems more plausible than the fasting state.

Food‐Drug Effects and Pediatric Drug Development Studies Submitted to the US Food and Drug Administration, 2012‐2022

“…Food instructions for drug products intended to be administered "without food" may be challenging for infants to adhere to since they are frequently fed and tend to remain in a semifed prandial state. 10 Other challenges are presented for drug products administered "with food," as labeling often does not specify what type of food to consume and infant diets do not resemble adult diets. The typical infant consumes a substantially higher number of calories from fat and carbohydrates compared with an adult, and feeds much more frequently (approx.…”

“…20 In another report, PBPK modeling was applied to 4 different BCS class I oral liquids to predict pediatric absorption with reasonable accuracy. 10 A recent FDA workshop summary concluded that "PBPK as an alternative bioequivalence approach and as a tool for risk assessment and biowaiver are increasingly seen in regulatory submissions." 21 In the future, modeling may represent an alternative approach to studying FE in pediatric patients.…”

“…Based on our study results, a majority of drugs with FE in adults were labeled for use in pediatric patients aged <2 years (35 of 47 for AUC inf , 75%; 45 of 56 for C max , 80%; Figure 2). Food instructions for drug products intended to be administered “without food” may be challenging for infants to adhere to since they are frequently fed and tend to remain in a semi‐fed prandial state 10 . Other challenges are presented for drug products administered “with food,” as labeling often does not specify what type of food to consume and infant diets do not resemble adult diets.…”

“…In 2018, investigators who developed a model for predicting the oral absorption of theophylline, paracetamol, and ketoconazole concluded that more information on the ontogeny of GI tract parameters was needed for model accuracy in predicting pediatric drug absorption 20 . In another report, PBPK modeling was applied to 4 different BCS class I oral liquids to predict pediatric absorption with reasonable accuracy 10 . A recent FDA workshop summary concluded that “PBPK as an alternative bioequivalence approach and as a tool for risk assessment and biowaiver are increasingly seen in regulatory submissions.” 21 In the future, modeling may represent an alternative approach to studying FE in pediatric patients.…”

Physiologically Based Pharmacokinetic Modeling of Nilotinib for Drug‐Drug Interactions, Pediatric Patients, and Pregnancy and Lactation

“…For the age group of 2‐6 years old in the study by Heimbach et al, 12 the absorption seems to follow another pattern compared to the older age groups and adults, as C max occurs at a relatively late time (around 7 hours, Figure 3a). While increasing the gastric emptying time can help to decrease the predicted C max and increase time to C max , 33 it remains questionable whether gastric emptying is slower in this age group of 2‐6‐year‐old children or whether other factors cause the apparently altered absorption pattern.…”