Factors affecting successful extrapolation of ibuprofen exposure from adults to paediatric populations after oral administration of a paediatric aqueous suspension
The importance of physiologically based pharmacokinetic (PBPK) model refinement for adults with data acquired in adults using a paediatric formulation under age-relevant dosing conditions in order to extrapolate drug exposure to infants was recently demonstrated for paracetamol. In the present investigation the aim was to expand the use of PBPK modeling informed by bioavailability data collected in healthy adults under different dosing conditions for a low solubility weak acid, ibuprofen, to simulate exposure across paediatric populations, i.e., infants, pre-school children, and schoolchildren. After developing and evaluating an adult disposition and oral absorption model for the aqueous suspension of ibuprofen, ibuprofen performance was extrapolated to paediatrics simulating exposure as a function of different prandial and dosing conditions: fasted conditions, reference-meal-fed conditions (solid-liquid meal), and infant-formula-fed conditions (homogeneous liquid). Successful predictions were achieved when employing the refined model for fasted or by applying appropriate fed conditions for different age groups, i.e., infant formula for infants and reference meal for children. The present study suggested that ibuprofen performance was primarily guided by gastric emptying events and showed sensitivity towards formulation characteristics and pH changes in the small intestine. Better understanding of luminal conditions’ changes in paediatrics and age-dependent ibuprofen post-absorptive processes could improve modeling confidence for ibuprofen, as well as other drugs with similar properties.
Physiologically based pharmacokinetic (PBPK) modeling, ibuprofen, infants, children, food effect, oral absorption
Κύρια θεματική κατηγορία:
Horizon 2020 Marie Skłodowska-Curie Innovative Training Networks programme under grant agreement No. 674909.