Age-dependent oral drug absorption in children: Assessment of a bottom-up modelling approach

Abstract

Paediatric drug development poses significant challenges due to the unique physiological and ethical considerations in children. Physiologically Based Pharmacokinetic (PBPK) modelling has emerged as a valuable tool for predicting paediatric drug absorption and optimising dosing strategies. This study aimed to refine PBPK modelling for paediatric applications by developing a customised PK-Sim-based paediatric PBPK (pPBPK) model for four drugs that are part of the Model List of Essential Medicines for Children by the World Health Organisation: paracetamol, ibuprofen, darunavir, and itraconazole. The model incorporated age-specific gastrointestinal parameters for four paediatric age groups, minimising the need for parameter interpolation or scaling. The effect of food on drug absorption was investigated by extending the absorption model to account for bile and excipient solubilisation. A literature review identified gaps in the understanding of paediatric intestinal parameters necessary for pPBPK modelling. Biorelevant in vitro dissolution and solubility data were integrated to enhance prediction accuracy. Validation with clinical pharmacokinetic data demonstrated the model’s reliability across different paediatric age groups. Sensitivity analyses highlighted the influence of gastric emptying time, small intestinal transit, and bile salt concentration on drug pharmacokinetics. This research underscores the potential of pPBPK modelling to inform paediatric dosing strategies while addressing current gaps and challenges.

Introduction

The lack of suitable paediatric medicines has long been a significant challenge. Despite regulatory efforts in the United States and the European Union since the early 2000s, including obligations, rewards and incentives to promote paediatric drug development, many therapeutic areas still lack appropriately tested and formulated medicines for children. This is due to several factors, most notably the unique challenges associated with paediatric drug therapy.

Age-related differences in drug absorption, distribution, metabolism, and excretion introduce significant variability in pharmacokinetics across the paediatric population. At the same time, children represent a highly vulnerable patient group, requiring stringent ethical and regulatory safeguards to minimise the risks involved in clinical pharmacokinetic studies. To address these challenges and support the development of safe and effective medicines for children, various extrapolation approaches are being explored. These include the use of pharmacokinetic modelling to minimize the need for extensive clinical studies in paediatric populations [1]. Traditional pharmacokinetic modelling is often based on extrapolation from adult data, which may not accurately capture the dynamic physiological changes that occur during childhood [2]. Accordingly, the validity of the corresponding models for the paediatric population is rather questionable. As a result, there is a critical need for paediatric-specific modelling approaches to guide safe and effective drug dosing in this vulnerable population. A recent article summarising the experience gained by the European Medicines Agency (EMA) on this topic even discusses that for very rare diseases with high medical need, a waiver of paediatric clinical trials based on population pharmacokinetics (PopPK) and/or physiology-based pharmacokinetic modelling (PBPK) may be possible [3]. This has led to a sharp increase in the use of paediatric PBPK (pPBPK) modelling in academia, the pharmaceutical industry and regulatory authorities. Overall, a 33-fold increase was reported between 2005 and 2020 [4]. The FDA reported that pPBPK modelling applications were used in 15 % and 9 % of the total applications received between 2008–2017 and 2018–2019, respectively [5,6].

Although pPBPK and PBPK have generally gained importance, they are mainly used for the prediction of PK covariates and population parameters that may affect dose selection, while formulation- and absorption modelling are only considered in very few studies [4,7]. The latter would be particularly important for children, where clinical or pharmacokinetic studies raise ethical concerns for several reasons, but where not only the administered drug dose and the dosage form, but also the mode of administration of a dosage form can differ significantly from drug administration to adults. In clinical studies in adults, an oral dosage form is usually administered with a glass of water on an empty stomach or after a standardised meal, which is very often a high-calorie, high-fat standard breakfast [8,9]. For children, there is no such standard protocol for clinical studies, which would also be difficult to implement given the wide age range covered by the term ‘children’. It is clear that the standard meal used in clinical studies with adults would be absolutely unsuitable for young children and that the amount of water to be administered with the dosage form would also have to be adapted to the age of the children. To improve the acceptance of oral medicines by children, the medications are often administered during a meal. Since, compared to fasted dosing, this mode of administration may affect the in vivo performance of a dosage form, it is equally important to consider both the quantity and characteristics of the meal administered and how this relates to the anatomy and physiology of the child in question when assessing the in vivo performance of a medicine.

According to the FDA’s Draft Guidance on “General Clinical Pharmacology Considerations for Pediatric Studies of Drugs, Including Biological Products”, if a medication formulation approved for use in adults is also intended for paediatric use, an additional food-effect study may not be required [10]. Likewise, if a paediatric formulation closely resembles the adult version and is approved based on in vitro dissolution tests, a separate food-effect study might not be necessary. However, it is important to bear in mind the physiological and nutritional differences between adults and children, including differences in the anatomy and function of the gastrointestinal tract. It is precisely because of these differences that extrapolation of food-drug interactions from adults to children, especially very young children, is not always appropriate.

PBPK modelling offers a promising approach in this case by capturing the complex interplay between drug properties, formulation characteristics, physiological factors, and dosing regimens in paediatric patients. Unlike traditional empirical approaches, PBPK models incorporate detailed anatomical, physiological, and biochemical parameters to simulate drug disposition across different age groups and developmental stages, providing valuable insights into paediatric pharmacokinetics [11]. However, detailed and reliable data on age-specific physiology, especially needed for modelling oral absorption, are currently sparse. Despite that fact, the fixed compartmental structure of many commercially available software solutions requires the input of a large number of physiological parameters, even when age-dependent data are lacking. In many cases these parameters are therefore estimated, assumed or scaled according to age, bodyweight or height, regardless of whether a relationship to any of these factors is known or not [12]. In addition to physiological changes, non-scalable factors such as specific diets and paediatric formulations pose challenges and limit the possibility of directly comparing and translating adult pharmacokinetic data to children.

According to a recent review of pPBPK model usage in clinical and drug development contexts, PK-Sim has emerged as the second-most widely used platform, following proprietary commercial software for pPBPK modelling [4]. This platform estimates absorption rates based on solubility and membrane affinity estimated from logP and molecular weight [13,14]. Additionally, it accounts for the diffusion of the drug molecules through the unstirred water layer.

However, particularly in the case of poorly soluble drugs, absorption is not only determined by these factors, but rather by a complex interplay of solubilisation, diffusion, distribution and permeation. Accordingly, an improvement in solubility does not necessarily result in increased absorption [15,16]. In its current form, the PK-Sim model does not account for the interplay between increased drug solubility mediated by food components, formulation excipients and bile salts, nor for the resulting effects on diffusion and permeation. This limitation is significant, as these interactions are considered fundamental to mechanistic absorption modelling and are essential for accurately estimating the impact of complex gastrointestinal contents, such as those present in different regions of the GI tract under fed or fasted conditions, on oral drug absorption [[17], [18], [19]].

This study aimed to address key gaps in paediatric pharmacokinetic modelling by developing a pPBPK model using PK-Sim for four drugs on the Model List of Essential Medicines for Children (EMLc) published by the World Health Organisation (WHO): paracetamol, ibuprofen, darunavir, and itraconazole. The initial step involved a comprehensive review of the current literature to assess the availability of reliable data on intestinal physiological parameters and their applicability in establishing a pPBPK model. Particular emphasis was placed on identifying knowledge gaps in order to reduce the reliance on parameter scaling and instead utilise robust in vivo data wherever possible. The identified data were then incorporated into the compartment structure of the PK-Sim-based pPBPK model. Both the model structure and absorption mechanism were modified from the standard PK-Sim model to allow investigation into the effects of excipients and food components on drug absorption. Following validation through comparison with available in vivo data, the model was further refined by integrating in vitro solubility- and dissolution data from a previously published study in biorelevant media designed to simulate postprandial intestinal conditions in pre-school children [20,21]. Finally, the potential of incorporating such biorelevant paediatric in vitro data into in the in silico model was evaluated with the aim of estimating the effects of co-administered child-specific meals on the absorption of the studied drugs in children of defined age groups.

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Fabian Winter, Jonas Lange, Sandra Klein, Age-dependent oral drug absorption in children: Assessment of a bottom-up modelling approach, European Journal of Pharmaceutics and Biopharmaceutics, Volume 214, 2025, 114815, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2025.114815.