Factors Affecting Successful Extrapolation of Ibuprofen Exposure from Adults to Pediatric Populations After Oral Administration of a Pediatric Aqueous Suspension

Abstract

The importance of physiologically based pharmacokinetic (PBPK) model refinement with data acquired in adults using a pediatric 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 evaluate the importance of similar PBPK model refinement for a low-solubility weak acid, ibuprofen, to simulate exposure across pediatric populations, i.e., infants, young children, and schoolchildren. After developing and evaluating adult disposition and oral absorption models for the aqueous suspension of ibuprofen, ibuprofen performance was extrapolated to pediatrics 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 state conditions or for fed state conditions relevant to specific 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 and showed sensitivity towards formulation characteristics and pH changes in the small intestine. Better understanding of luminal conditions in pediatrics and age-dependent ibuprofen post-absorptive processes could improve modeling confidence for ibuprofen, as well as other drugs with similar characteristics.

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Acknowledgments

The authors would like to thank biorelevant.com for providing the SIF powder for the preparation of biorelevant media and to express their gratitude to SimulationsPlus Inc., for providing access to GastroPlus™ 9.7.

Funding

This work has received funding from the Horizon 2020 Marie Skłodowska-Curie Innovative Training Networks program under grant agreement no. 674909.

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Statelova, M., Holm, R., Fotaki, N. et al. Factors Affecting Successful Extrapolation of Ibuprofen Exposure from Adults to Pediatric Populations After Oral Administration of a Pediatric Aqueous Suspension. AAPS J 22, 146 (2020). https://doi.org/10.1208/s12248-020-00522-4

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KEY WORDS

  • children
  • food effect
  • ibuprofen
  • infants
  • oral absorption
  • physiologically based pharmacokinetic (PBPK) modeling