Physiologically-Based Biopharmaceutics Modeling for Ibuprofen: Identifying Key Formulation Parameter and Virtual Bioequivalence Assessment
Abstract
:1. Introduction
2. Materials and Methods
2.1. PBPK Model Variability Optimization
2.2. PBBM Model Development and Verification
2.3. PBBM/PBPK Framework Application
3. Results
3.1. PBPK Model Variability Optimization
3.2. PBBM Model Development and Verification
3.3. PBBM Model Application
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ADAM | Advanced Dissolution, Absorption, and Metabolism |
ADME | Absorption, distribution, metabolism, and excretion |
BCS | Biopharmaceutics Classification System |
BE | Bioequivalence |
BSV | Between-subject variability |
CI | Confidence interval |
Cmax | Maximum concentration |
CV (%) | Coefficient of variation |
DLM | Diffusion layer model |
GI | Gastrointestinal |
GSA | Global sensitivity analysis |
IV | Intravenous |
IVIV | In vitro–in vivo |
MB7 | Maleate buffer 7 mM |
MRT | Mean residence time |
PB5 | Phosphate buffer 5 mM |
PB50 | Phosphate buffer 50 mM |
PBBM | Physiologically based biopharmaceutics model(ing) |
PBPK | Physiologically based pharmacokinetic |
PE | Prediction error |
PK | Pharmacokinetic |
SI | Small intestine |
SIVA | SimCyp® In Vitro Data Analysis toolkit |
T/R | Test/reference |
VBE | Virtual bioequivalence |
Vss | Steady-state volume of distribution |
WSV | Within-subject variability |
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Selected Parameter | Variation (CV (%)) | Minimum Limit | Parameter Value | Maximum Limit |
---|---|---|---|---|
Fasted MRT stomach fluid * | 150 | 0.01 | 0.12 | 12 |
Fasted MRT SI fluid * | 150 | 0.5 | 3.4 | 12 |
pH fasted duodenum | 16 | 0 | 6.4 | 15 |
pH fasted jejunum 1 | 13 | 0 | 6.5 | 15 |
pH fasted jejunum 2 | 11 | 0 | 6.6 | 15 |
pH fasted ileum 1 | 10 | 0 | 6.8 | 15 |
pH fasted ileum 2 | 10 | 0 | 7 | 15 |
pH fasted ileum 3 | 7 | 0 | 7.1 | 15 |
pH fasted ileum 4 | 6 | 0 | 7.3 | 15 |
pH fasted colon | 13 | 3.18 | 6.6 | 9.8 |
Initial volume of stomach fluid fasted | 30 | 20 | 50 | 1000 |
Total Jej1 Ile4 volume fasted | 30 | 10 | 105 | 1000 |
Colon volume fasted | 0 | 1 | 13 | 250 |
Vss (user input) treatment 1 * | 10 | 0.05 | 0.091249 | 1000 |
Vss (user input) treatment 2 * | 10 | 0.05 | 0.091249 | 1000 |
Fasted MRT stomach fine particles treatment 1 * | 150 | 0.01 | 0.27 | 12 |
Fasted MRT SI fine particles treatment 1 * | 150 | 0.5 | 3.4 | 12 |
Fasted MRT stomach fine particles treatment 2 * | 150 | 0.01 | 0.27 | 12 |
Fasted MRT SI fine particles treatment 2 * | 150 | 0.5 | 3.4 | 12 |
Variability | Enantiomer | IV | Solution | Suspension | Soft Gelatin Capsules | Tablets | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
Obs | Pred | Obs | Pred | Obs | Pred | Obs | Pred | Obs | Pred | ||
WSV | R | 15.63 | 16.73 | 15.63 | 19.73 | 14.25 | 14.65 | 16.05 | 15.55 | 14.90 | 15.83 |
S | 16.93 | 17.98 | 16.93 | 20.05 | 13.35 | 14.95 | 16.00 | 15.55 | 12.15 | 16.60 | |
BSV | R | 17.05 | 16.63 | 22.03 | 23.68 | 25.10 | 23.30 | 18.20 | 23.80 | 21.90 | 19.93 |
S | 16.23 | 19.43 | 19.38 | 24.55 | 22.30 | 22.70 | 18.35 | 23.35 | 20.40 | 21.67 |
Pretreatment | Treatment | Reference Product | Test Product | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Medium | pH | Particle Surface pH | r2 | Cmax PE | Δ tmax (%) | Particle Surface pH | r2 | Cmax PE | Δ tmax (%) | |
None | PB50 | 6.8 | 5.71 | 0.93 | 0.96 | 50 | 5.85 | 0.95 | 1.14 | −40 |
HCl (pH 1.2) | PB50 | 6.8 | 6.29 * | 0.91 | 1.13 | 25 | 6.25 * | 0.95 | 1.24 | −50 |
HCl (pH 2.0) | PB50 | 6.8 | 6.30 * | 0.94 | 1.13 | 25 | 6.20 * | 0.95 | 1.24 | −50 |
None | PB5 | 6.7 | 5.81 | 0.97 | 1.01 | 50 | 5.58 | 0.96 | 0.99 | −30 |
HCl (pH 1.2) | PB5 | 6.7 | 6.28 * | 0.92 | 1.13 | 25 | 5.30 * | 0.96 | 0.80 | −7 |
HCl (pH 2.0) | PB5 | 6.7 | 6.25 * | 1.00 | 1.12 | 25 | 5.42 * | 0.95 | 0.89 | −20 |
None | MB7 | 6.5 | 5.64 | 0.97 | 0.93 | 75 | 5.40 | 0.91 | 0.87 | −20 |
HCl (pH 1.2) | MB7 | 6.5 | 6.33 * | 0.94 | 1.13 | 25 | 5.49 * | 0.95 | 0.93 | −20 |
HCl (pH 2.0) | MB7 | 6.5 | 6.02 * | 0.99 | 1.09 | 25 | 5.57 * | 0.98 | 0.98 | −30 |
Enantiomer | Test Product Particle Surface pH | Predicted | Calculated Sample Size | Calculated 90% CI | ||
---|---|---|---|---|---|---|
Cmax GMR | 80% Power | 90% Power | LL | UL | ||
R-ibuprofen | 5.64 | 84.00 | 114 | 158 | 81.31 | 86.78 |
R-ibuprofen | 5.66 | 85.00 | 74 | 104 | 81.62 | 88.52 |
R-ibuprofen | 5.70 | 87.00 | 40 | 54 | 82.28 | 92.00 |
R-ibuprofen | 5.75 | 90.00 | 20 | 28 | 82.98 | 97.61 |
R-ibuprofen | 5.80 | 93.00 | 12 | 18 | 83.35 | 103.77 |
R-ibuprofen | 5.85 | 95.00 | 10 | 14 | 83.99 | 107.45 |
S-ibuprofen | 5.64 | 85.00 | 64 | 88 | 81.66 | 88.48 |
S-ibuprofen | 5.66 | 86.00 | 44 | 62 | 81.91 | 90.29 |
S-ibuprofen | 5.70 | 87.00 | 34 | 46 | 82.28 | 91.99 |
S-ibuprofen | 5.73 | 90.00 | 18 | 24 | 83.16 | 97.40 |
S-ibuprofen | 5.80 | 93.00 | 12 | 14 | 84.11 | 102.84 |
S-ibuprofen | 5.84 | 95.00 | 8 | 12 | 83.25 | 108.41 |
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Zarzoso-Foj, J.; Cuquerella-Gilabert, M.; Merino-Sanjuan, M.; Reig-Lopez, J.; Mangas-Sanjuán, V.; Garcia-Arieta, A. Physiologically-Based Biopharmaceutics Modeling for Ibuprofen: Identifying Key Formulation Parameter and Virtual Bioequivalence Assessment. Pharmaceutics 2025, 17, 408. https://doi.org/10.3390/pharmaceutics17040408
Zarzoso-Foj J, Cuquerella-Gilabert M, Merino-Sanjuan M, Reig-Lopez J, Mangas-Sanjuán V, Garcia-Arieta A. Physiologically-Based Biopharmaceutics Modeling for Ibuprofen: Identifying Key Formulation Parameter and Virtual Bioequivalence Assessment. Pharmaceutics. 2025; 17(4):408. https://doi.org/10.3390/pharmaceutics17040408
Chicago/Turabian StyleZarzoso-Foj, Javier, Marina Cuquerella-Gilabert, Matilde Merino-Sanjuan, Javier Reig-Lopez, Víctor Mangas-Sanjuán, and Alfredo Garcia-Arieta. 2025. "Physiologically-Based Biopharmaceutics Modeling for Ibuprofen: Identifying Key Formulation Parameter and Virtual Bioequivalence Assessment" Pharmaceutics 17, no. 4: 408. https://doi.org/10.3390/pharmaceutics17040408
APA StyleZarzoso-Foj, J., Cuquerella-Gilabert, M., Merino-Sanjuan, M., Reig-Lopez, J., Mangas-Sanjuán, V., & Garcia-Arieta, A. (2025). Physiologically-Based Biopharmaceutics Modeling for Ibuprofen: Identifying Key Formulation Parameter and Virtual Bioequivalence Assessment. Pharmaceutics, 17(4), 408. https://doi.org/10.3390/pharmaceutics17040408