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Using Physiologically Based Pharmacokinetic (PBPK) Modelling to Gain Insights into the Effect of Physiological Factors on Oral Absorption in Paediatric Populations

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Paediatric pharmaceutics has become an important topic, but currently, there is an incomplete knowledge of paediatric gastrointestinal physiology and adequate biopharmaceutical tools still have to be developed. The present study aimed to increase the understanding of oral drug absorption in paediatric populations by using physiologically based pharmacokinetic (PBPK) modelling and in vitro dissolution testing. The oral absorption of two model compounds, sotalol and paracetamol, was studied by collection of reported pharmacokinetic profiles from adult and paediatric subjects. A PBPK model based on input parameters collected from the literature was first developed and validated in adults before being extrapolated to paediatric age groups. The accuracy of the model simulations was assessed by comparison to the observed pharmacokinetic profiles, and in the case of discrepancy, further investigations were made via parameter sensitivity analysis and in vitro dissolution testing. The PBPK models accurately predicted sotalol and paracetamol exposure in adult populations. An accurate simulation was also obtained after model extrapolation to children older than 2 years of age. However, the simulation in infants and newborns resulted in a discrepancy, which was further analysed. Dissolution testing suggested no significant difference in the drug release rate between paediatric and adult age groups. In contrast, mean gastric emptying time seemed to be underestimated in infants and newborns, and optimisation of this input parameter improved the prediction of the model. Considering age-specific differences in gastrointestinal tract physiology should improve prediction of drug absorption in paediatric patients.

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Active pharmaceutical ingredient


Area under the curve


Blood to plasma concentration ratio


Body surface area


Centers for Disease Control and Prevention

C max :

Maximal concentration of the plasma concentration-time curve




Fasted state simulated intestinal fluid


Fed state simulated intestinal fluid


Fraction unbound


European Medicines Agency


Mean gastric transit time




Hydrochloric acid


High-performance liquid chromatography


International Conference on Harmonisation



KH2PO4 :

Potassium dihydrogen phosphate

K p :

Partition coefficient


Molecular weight


Sodium chloride


Sodium dihydrogen phosphate monohydrate


Sodium hydroxide


Physiologically based pharmacokinetic



pKa :

Acid dissociation constant






Parameter sensitivity analysis

ratio(Obs/Pred) :

Observed to predicted ratio


Standard deviation

SGFsp :

Simulated gastric fluid without pepsin


Small intestine


Small intestinal transit time


Trifluoroacetic acid

t max :

Time to reach the maximal concentration

V ss :

Volume of distribution at steady state


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Villiger, A., Stillhart, C., Parrott, N. et al. Using Physiologically Based Pharmacokinetic (PBPK) Modelling to Gain Insights into the Effect of Physiological Factors on Oral Absorption in Paediatric Populations. AAPS J 18, 933–947 (2016).

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