Successful extrapolation of paracetamol exposure from adults to infants after oral administration of a paediatric aqueous suspension is highly dependent on the study dosing conditions
Extending licensed drug use to the pediatric population has become an essential part of the drug development process. Nonetheless ethical concerns limit clinical testing in paediatric populations and data collected from oral bioavailability and food effect studies in adults are often extrapolated to the target paediatric (sub)populations. However, based on published information, food effects on drug absorption in infants may not be adequately evaluated by data collected in adults. In the present study, a physiologically based pharmacokinetic (PBPK) approach for modeling paracetamol suspension data collected in adults was proposed with the ultimate aim to investigate whether extrapolation to infants is substantially affected by the dosing conditions applied to adults. The development of the PBPK model for adults was performed using GastroPlus™ and, after scaling to infants considering physiological, anatomical, and drug clearance changes, extrapolation of the different dosing conditions was performed by applying dosing conditions dependent changes on the paracetamol gastric emptying process. Successful predictions of observed plasma concentration levels in infants were achieved when extrapolating from fasted and infant-formula-fed conditions data. Data collected following the reference meal appeared less useful for simulating paracetamol suspension performance in infants. The proposed methodology deserves further evaluation using high-quality clinical data both in adults and in infants.
Physiologically based pharmacokinetic (PBPK) modeling, paediatrics, infants, food effect, oral absorption, paracetamol
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This work has received funding from Horizon 2020 Marie Sklodowska-Curie Innovative Training Networks programme under grant agreement No. 674909