Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging
Abstract
:1. Introduction
2. Materials and Methods
2.1. API and Formulation Properties
2.2. Clinical Pharmacokinetic Data of Basmisanil
2.3. Construction of the Baseline GastroPlus™ Model
2.4. Food Effect Modeling Approach
2.5. Parameter Sensitivity Analysis
3. Results
3.1. Simulations for Uncoated Tablet Formulation at a Dose of 660 mg
3.2. Model Parameter Sensitivity Analysis at a Dose of 660 mg
3.3. GastroPlus™ Model Simulations for Granules at a Dose of 120 mg
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Parameter * | Value |
---|---|
Molecular weight | 445.5 g/mol |
pKa | 2.07 (base) |
logD (pH 7.4) | 1.86 |
Melting point | 148.3 °C |
Blood/plasma concentration ratio Fraction of drug unbound in plasma | 0.59 5.6% |
Solubility at 25 °C | |
Aqueous buffer pH 1–9 Solubility at 37 °C | 0.001 mg/mL |
SGF pH 1.6 | 0.008 mg/mL |
FaSSIF pH 6.5 | 0.010 mg/mL |
FeSSIF pH 5 | 0.032 mg/mL |
Particle size distribution | |
D10 | 1.4 μm |
D50 | 4.7 μm |
D90 | 10.1 μm |
Effective human jejunal permeability | 3.75 × 10−4 cm/s |
Disposition model parameters | |
k12 | 1.294 1/h |
k21 | 0.979 1/h |
k10 | 0.245 1/h |
Vc/kg | 0.235 L/kg |
V2/kg | 0.311 L/kg |
CL/kg | 0.058 L/h/kg |
CL2/kg | 0.304 L/h/kg |
Elimination half-life | 7.0 h |
Fasted State | Fed State | |||||
---|---|---|---|---|---|---|
Parameters | Observed | Simulated | Simulated/Observed | Observed | Simulated | Simulated/Observed |
Cmax (ng/mL) | 1649 | 1648 | 0.999 | 3787 | 2892 | 0.764 |
AUCinf (ng.h/mL) | 51,400 | 42,600 | 0.829 | 76,900 | 60,500 | 0.786 |
Tmax (h) | 4 | 5.74 | 1.435 | 4 | 5.64 | 1.410 |
Parameters | Fasted State | Fed State | ||||
---|---|---|---|---|---|---|
Parameter Range Explored (Baseline) | Cmax (ng/mL) | AUC(0-inf) (ng.h.mL) | Parameter Range Explored (Baseline) | Cmax (ng/mL) | AUC(0-inf) (ng.h.mL) | |
Peff | 1.87–7.5 (3.75) | 60.4–153 | 62.6–148 | 1.87–7.5 (3.75) | 61.5–150 | 64.3–143 |
Particle size (D50) | 0.78–7.05 (2.35) | 109–79.5 | 108–83.5 | 0.78–7.05 (2.35) | 113.7–76.7 | 111–81.3 |
Bile salt Solubiliza-tion Ratio | 323–2897.1 (965.7) | 98.9–103 | 99.5–102 | 2917–26,300 (8753.6) | 72.4–173 | 81.6–145 |
Stomach pH | 0.5–5 (1.3) | 102–88.1 | 101–90.8 | 4–6 (4.9) | 100–99.9 | 99.9–99.9 |
Fasted State | Fed State | |||||
---|---|---|---|---|---|---|
Parameters | Observed | Simulated | Simulated/Observed | Observed | Simulated | Simulated/Observed |
Cmax (ng/mL) | 1043 | 1006 | 0.96 | 1513 | 1877 | 1.2 |
AUCinf (ng.h/mL) | 16,010 | 20,760 | 1.3 | 24,050 | 26,090 | 1.1 |
Tmax (h) | 3 | 4.26 | 1.4 | 4 | 3.94 | 0.99 |
Formulation | Simulated | Observed * | Ratio of Simulated/Observed Food Effect | |||
---|---|---|---|---|---|---|
Cmax | AUC | Cmax | AUC | Cmax | AUC | |
660 mg uncoated tablets | 1.75 | 1.42 | 2.31 | 1.52 | 0.76 | 0.93 |
120 mg granules | 1.86 | 1.25 | 1.38 | 1.5 | 1.35 | 0.83 |
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Belubbi, T.; Bassani, D.; Stillhart, C.; Parrott, N. Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging. Pharmaceutics 2023, 15, 191. https://doi.org/10.3390/pharmaceutics15010191
Belubbi T, Bassani D, Stillhart C, Parrott N. Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging. Pharmaceutics. 2023; 15(1):191. https://doi.org/10.3390/pharmaceutics15010191
Chicago/Turabian StyleBelubbi, Tejashree, Davide Bassani, Cordula Stillhart, and Neil Parrott. 2023. "Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging" Pharmaceutics 15, no. 1: 191. https://doi.org/10.3390/pharmaceutics15010191
APA StyleBelubbi, T., Bassani, D., Stillhart, C., & Parrott, N. (2023). Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging. Pharmaceutics, 15(1), 191. https://doi.org/10.3390/pharmaceutics15010191