title: Using Physiologically Based Pharmacokinetic (PBPK) Modelling to Gain Insights into the Effect of Physiological Factors on Oral Absorption in Paediatric Populations.
abstract: 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.
authors.affiliation: Formulation Research & Development, F. Hoffmann - La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland.|Institute of Pharmaceutical Technology, University of Applied Sciences and Arts Northwestern Switzerland, Gründenstrasse 40, 4132, Muttenz, Switzerland.
authors.forename: Angela
authors.initials: A
authors.lastname: Villiger
authors.affiliation: Formulation Research & Development, F. Hoffmann - La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Cordula
authors.initials: C
authors.lastname: Stillhart
authors.affiliation: Pharmaceutical Research & Early Development, Pre-Clinical CMC, Roche Innovation Center Basel, F. Hoffmann - La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Neil
authors.initials: N
authors.lastname: Parrott
authors.affiliation: Institute of Pharmaceutical Technology, University of Applied Sciences and Arts Northwestern Switzerland, Gründenstrasse 40, 4132, Muttenz, Switzerland. martin.kuentz@fhnw.ch.
authors.forename: Martin
authors.initials: M
authors.lastname: Kuentz
mesh_terms: D000284:Administration, Oral; D002648:Child; D003198:Computer Simulation; D041981:Gastrointestinal Tract; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D008954:Models, Biological; D013015:Sotalol / Q000494:pharmacology
chemical_list: D013015:Sotalol
keywords: in vitro dissolution; mean gastric transit time; oral drug absorption; paediatric PBPK modelling; paediatric gastrointestinal physiology