Successful Extrapolation of Paracetamol Exposure from Adults to Infants After Oral Administration of a Pediatric Aqueous Suspension Is Highly Dependent on the Study Dosing Conditions

Statelova, Marina; Holm, René; Fotaki, Nikoletta; Reppas, Christos; Vertzoni, Maria

doi:10.1208/s12248-020-00504-6

Cited by 11 publications

(46 citation statements)

References 67 publications

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“…Consequently, the presented pediatric PBPK model for acetaminophen incorporating a fasted state could not adequately predict the absorption profile (Figure 1) and an increased gastric emptying time—secondary to food intake—could better predict acetaminophen absorption (Table 2). These findings are consistent with those of a recently published modeling study for acetaminophen 63 …”

Section: Discussionsupporting

confidence: 93%

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

Liu

Anker

Burckart

et al. 2021

The Journal of Clinical Pharma

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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.

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Section: Discussionsupporting

confidence: 93%

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

Liu

Anker

Burckart

et al. 2021

The Journal of Clinical Pharma

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“…The remaining PBK model results were obtained from different scientific publications. In case of acetaminophen, the data were obtained from (Gaohua et al 2016;Mian et al 2020;Pearce et al 2017b;Statelova et al 2020). For caffeine, the PBK-predicted plasma levels were obtained from (Gajewska et al 2014;Gaohua et al 2016;Mian et al 2020;Pearce et al 2017b) and for coumarin from (Gajewska et al 2014;Moxon et al 2020;Pearce et al 2017b).…”

Section: Important Input Parametersmentioning

confidence: 99%

Towards best use and regulatory acceptance of generic physiologically based kinetic (PBK) models for in vitro-to-in vivo extrapolation (IVIVE) in chemical risk assessment

et al. 2022

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With an increasing need to incorporate new approach methodologies (NAMs) in chemical risk assessment and the concomitant need to phase out animal testing, the interpretation of in vitro assay readouts for quantitative hazard characterisation becomes more important. Physiologically based kinetic (PBK) models, which simulate the fate of chemicals in tissues of the body, play an essential role in extrapolating in vitro effect concentrations to in vivo bioequivalent exposures. As PBK-based testing approaches evolve, it will become essential to standardise PBK modelling approaches towards a consensus approach that can be used in quantitative in vitro-to-in vivo extrapolation (QIVIVE) studies for regulatory chemical risk assessment based on in vitro assays. Based on results of an ECETOC expert workshop, steps are recommended that can improve regulatory adoption: (1) define context and implementation, taking into consideration model complexity for building fit-for-purpose PBK models, (2) harmonise physiological input parameters and their distribution and define criteria for quality chemical-specific parameters, especially in the absence of in vivo data, (3) apply Good Modelling Practices (GMP) to achieve transparency and design a stepwise approach for PBK model development for risk assessors, (4) evaluate model predictions using alternatives to in vivo PK data including read-across approaches, (5) use case studies to facilitate discussions between modellers and regulators of chemical risk assessment. Proof-of-concepts of generic PBK modelling approaches are published in the scientific literature at an increasing rate. Working on the previously proposed steps is, therefore, needed to gain confidence in PBK modelling approaches for regulatory use.

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“…The development of age-appropriate biorelevant in vitro (solubility and dissolution testing) and in silico tools (such as PBPK modelling) is beneficial for the prediction of the in vivo performance in pediatric patients. Recently, an integrated in vivo and in silico approach has also been described for infants (17)(18)(19), which focused on the design of in vivo adult studies that employ dosing conditions representative of infants. The obtained in vivo data was then leveraged to extrapolate drug product performance from adults to infants (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, an integrated in vivo and in silico approach has also been described for infants (17)(18)(19), which focused on the design of in vivo adult studies that employ dosing conditions representative of infants. The obtained in vivo data was then leveraged to extrapolate drug product performance from adults to infants (17)(18)(19). PBPK modelling promotes the mechanistic understanding of formulation performance in pediatric subgroups by allowing incorporation of the knowledge on anatomy and physiology as a function of growth and development (20).…”

Section: Introductionmentioning

confidence: 99%

Performance Evaluation of Montelukast Pediatric Formulations: Part II — a PBPK Modelling Approach

Guimarães

Vertzoni

Fotaki

2022

AAPS J

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This study aimed to build a physiologically based pharmacokinetic (PBPK) model coupled with age-appropriate in vitro dissolution data to describe drug performance in adults and pediatric patients. Montelukast sodium was chosen as a model drug. Two case studies were investigated: case study 1 focused on the description of formulation performance from adults to children; case study 2 focused on the description of the impact of medicine co-administration with vehicles on drug exposure in infants. The PBPK model for adults and pediatric patients was developed in Simcyp® v18.2 informed by age-appropriate in vitro dissolution results obtained in a previous study. Oral administration of montelukast was simulated with the ADAM™ model. For case study 1, the developed PBPK model accurately described montelukast exposure in adults and children populations after the administration of montelukast chewable tablets. Two-stage dissolution testing in simulated fasted gastric to intestinal conditions resulted in the best description of in vivo drug performance in adults and children. For case study 2, a good description of in vivo drug performance in infants after medicine co-administration with vehicles was achieved by incorporating in vitro drug dissolution (under simulated fasted gastric to fed intestinal conditions) into a fed state PBPK model with consideration of the in vivo dosing conditions (mixing of formulation with applesauce or formula). The case studies presented demonstrate how a PBPK absorption modelling strategy can facilitate the description of drug performance in the pediatric population to support decision-making and biopharmaceutics understanding during pediatric drug development. Graphical abstract

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Successful Extrapolation of Paracetamol Exposure from Adults to Infants After Oral Administration of a Pediatric Aqueous Suspension Is Highly Dependent on the Study Dosing Conditions

Cited by 11 publications

References 67 publications

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

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

Towards best use and regulatory acceptance of generic physiologically based kinetic (PBK) models for in vitro-to-in vivo extrapolation (IVIVE) in chemical risk assessment

Performance Evaluation of Montelukast Pediatric Formulations: Part II — a PBPK Modelling Approach

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