Model-Based Prediction of Acid Suppression and Proposal of a New Dosing Regimen of Fexuprazan in Humans
Abstract
:1. Introduction
2. Materials and Methods
2.1. Pharmacokinetic Analysis
2.1.1. Moment Analysis
2.1.2. One-Compartment Model
2.1.3. Physiologically Based Pharmacokinetic (PBPK) Model
2.2. Pharmacodynamic Analysis
2.2.1. Indirect Response Model
2.2.2. Simple Direct Effect Model
2.3. Pharmacokinetic–Pharmacodynamic Modeling
2.4. Statistics
3. Results
3.1. Pharmacokinetic Analysis
3.2. Pharmacodynamic Models
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Scenario | Pharmacokinetic Model | Pharmacodynamic Model |
---|---|---|
A | One-compartment (plasma) | Indirect response |
B | PBPK (plasma) | Indirect response |
C | PBPK (stomach) | Indirect response |
D | PBPK (stomach) | Simple direct effect |
Parameter (Unit) | Group | 20 mg QD | 40 mg QD | 80 mg QD | |
---|---|---|---|---|---|
AUCτ (min × ng/mL) | Observed | Training set | 1.36 × 104 ± 9.65 × 103 | 2.51 × 104 ± 6.12 × 103 | 5.91 × 104 ± 2.08 × 104 |
Validation set | - | 2.34 × 104 ± 1.16 × 104 | 5.18 × 104 ± 1.87 × 104 | ||
Simulated | Compartment model | 1.32 × 104 | 2.65 × 104 | 5.30 × 104 | |
PBPK model | 1.49 × 104 | 3.00 × 104 | 6.04 × 104 | ||
AUCratio | Compartment model | 1.03 | 0.947 | 1.12 | |
- | 0.883 | 0.977 | |||
PBPK model | 0.913 | 0.837 | 0.978 | ||
- | 0.780 | 0.858 | |||
Cmax,SS (ng/mL) | Observed | Training set | 20.8 ± 14.4 | 43.2 ± 11.6 | 94.4 ± 36.5 |
Validation set | - | 35.5 ± 19.3 | 78.9 ± 34.0 | ||
Simulated | Compartment model | 19.0 | 37.9 | 75.9 | |
PBPK model | 20.2 | 40.4 | 81.2 | ||
Cmax,ratio | Compartment model | 1.09 | 1.14 | 1.24 | |
- | 0.937 | 1.04 | |||
PBPK model | 1.03 | 1.07 | 1.16 | ||
- | 0.878 | 0.972 |
Scenario | Parameter | Value |
---|---|---|
A | pHbaseline | 1.30 |
kin (pOH/min) | 0.132 | |
Imax (ratio) | 0.386 | |
IC50 (ng/mL) | 1.06 | |
γ | 2.51 | |
B | pHbaseline | 1.22 |
kin (pOH/min) | 0.139 | |
Imax (ratio) | 0.401 | |
IC50 (ng/mL) | 1.16 | |
γ | 2.14 | |
C | pHbaseline | 1.29 |
kin (pOH/min) | 1760 | |
Imax (ratio) | 0.378 | |
IC50 (ng/g tissue) | 0.919 | |
γ | 2.16 | |
D | pHbaseline | 1.04 |
Emax (pH) | 5.50 | |
1.58 | ||
EC50 (ng/g tissue) | 0.992 |
Scenario | Scenario A | Scenario B | Scenario C | Scenario D |
---|---|---|---|---|
Fold difference | 1.00 (0.572, 1.64) | 0996 (0.688, 1.67) | 0.992 (0.691, 1.59) | 0.988 (0.696, 1.62) |
RMSLE | 0.315 | 0.262 | 0.243 | 0.249 |
RMSE | 0.992 | 0.800 | 0.853 | 0.845 |
r2 | 0.738 | 0.827 | 0.803 | 0.808 |
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Kim, M.-S.; Lee, N.; Lee, A.; Chae, Y.-J.; Chung, S.-J.; Lee, K.-R. Model-Based Prediction of Acid Suppression and Proposal of a New Dosing Regimen of Fexuprazan in Humans. Pharmaceuticals 2022, 15, 709. https://doi.org/10.3390/ph15060709
Kim M-S, Lee N, Lee A, Chae Y-J, Chung S-J, Lee K-R. Model-Based Prediction of Acid Suppression and Proposal of a New Dosing Regimen of Fexuprazan in Humans. Pharmaceuticals. 2022; 15(6):709. https://doi.org/10.3390/ph15060709
Chicago/Turabian StyleKim, Min-Soo, Nora Lee, Areum Lee, Yoon-Jee Chae, Suk-Jae Chung, and Kyeong-Ryoon Lee. 2022. "Model-Based Prediction of Acid Suppression and Proposal of a New Dosing Regimen of Fexuprazan in Humans" Pharmaceuticals 15, no. 6: 709. https://doi.org/10.3390/ph15060709