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Physiologically-Based Biopharmaceutics Modeling for Ibuprofen: Identifying Key Formulation Parameter and Virtual
Javier Zarzoso-Foj1,2, Marina Cuquerella-Gilabert1,2, Matilde Merino-Sanjuan1,2
1Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46010 Valencia, Spain.
Pharmaceutics
|April 26, 2025
Summary
Physiologically based biopharmaceutics modeling (PBBM) identified ibuprofen particle surface pH as key for dissolution. This enables defining an in vitro safe space for predicting bioequivalence (BE) and optimizing virtual BE studies.
Area of Science:
- Pharmacokinetics and Biopharmaceutics
- Computational Modeling and Simulation
Background:
- Physiologically based pharmacokinetic (PBPK) modeling, specifically physiologically based biopharmaceutics modeling (PBBM), offers mechanistic insights into drug disposition.
- PBBM facilitates prediction of bioequivalence (BE) outcomes and defines operational 'safe spaces'.
- Existing PBPK models require refinement for accurate prediction of in vitro safe spaces and virtual BE (VBE) for immediate-release (IR) ibuprofen tablets.
Purpose of the Study:
- To identify the product-related parameter governing ibuprofen dissolution.
- To enhance an existing PBPK model for ibuprofen IR tablets.
- To establish an in vitro safe space and perform virtual BE (VBE) predictions.
Main Methods:
- Optimized Cmax variability using previous PBPK model parameters.
- Identified key physiological parameters for ibuprofen absorption and disposition.
- Modeled in vitro dissolution data to determine the critical dissolution parameter.
- Defined an in vitro safe space and calculated sample size for BE declaration.
- Conducted VBE simulations to assess the impact of sample size and trial design.
Main Results:
- Adjusted stomach and small intestine Vss and MRT CV (%) to 10% and 150% respectively, adequately predicting Cmax variability.
- Identified particle surface pH as the critical parameter influencing ibuprofen dissolution.
- Established an in vitro safe space for test product surface pH (5.64-6.40) to ensure 90% CIs for Cmax ratio within 80-125% for a reference product pH of 6.02.
- R-ibuprofen was identified as the most discriminative enantiomer.
- VBE simulations with 24 subjects indicated sensitivity of BE outcomes to the number of trial replicates and runs.
Conclusions:
- Ibuprofen particle surface pH is the key in vitro parameter controlling dissolution under specific conditions (maleate buffer, HCl pretreatment).
- An in vitro safe space was established, aiding sample size calculations for BE studies.
- PBBM/PBPK model-informed VBE simulations provide a valuable tool for evaluating BE success rates and optimizing trial design.
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