Accelerating Development of Benziamidazole-Class Proton Pump Inhibitors: A Mechanism-Based PK/PD Model to Optimize Study Design with Ilaprazole as a Case Drug
Abstract
:1. Introduction
2. Materials and Methods
2.1. Date Source
2.2. Methodology
2.3. Pharmacokinetic Modeling
2.4. Pharmacodynamics Modeling
2.5. Model Evaluation and Validation
2.6. Investigation of the “Ceiling Effect” of Ilaprazole
2.7. Optimization of Dose Regimens
3. Results
3.1. PK Model Development and Estimation
3.2. PD Model Development and Estimation
3.3. Model Evaluation and Validation
3.4. Investigation of the “Ceiling Effect” of Ilaprazole
3.5. Optimization of Dose Regimens
4. Discussion
4.1. Establishment and Validation of the Mechanism-Based PK/PD Model
4.2. Assessment of the Mechanism-Based PK/PD Model under a Wide Range of Dosing Regimens
4.3. Investigation of the Potential “Ceiling Effect” of PPIs
4.4. Optimization of Dose Regimens
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 | Unit | Definition | Estimate | 95CI% | η |
---|---|---|---|---|---|
CLp | L/h | Clearance from the central compartment | 2.57 | (2.34, 2.81) | 0.23 |
CLt | L/h | Clearance from the central compartment to the peripheral Compartment | 4.59 | (4.22, 5) | 1.17 |
VC | L | Distribution volume of central compartment | 8.80 | (8.58, 9.02) | 0.062 |
VP | L | Distribution volume of peripheral compartment | 3.65 | (3.63, 3.67) | 0.29 |
θwt | Fixed effect of body weight | 1.35 | (1.31, 1.39) | - | |
θsex | Fixed effect of gender | 1.30 | (1.14, 1.48) | - | |
Proportional residual error | 0.12 | - | - |
Parameter | Unit | Definition | Estimate | RSE% | η |
---|---|---|---|---|---|
kdeg | 1/h | H+/K+-ATPase degradation rate constant | 0.15 | 21.05 | 2.61 |
kd | (ng/mL)/h | Irreversible inhibition efficacy of H+/K+-ATPase by ilaprazole | 18.24 | 12.24 | 1.38 |
Elimination rate constant for intra-gastric H+ concentration | |||||
kout | 1/h | Baseline of intra-gastric H+ concentration | 5.6 | 11.52 | 1.32 |
Base | mM | Width of the night intra-gastric H+ surge | 0.033 | Fixed | - |
MW | h | Amplitude of the night intra-gastric H+ surge | 0.99 | 30.18 | - |
MA | Peak time of the night intra-gastric H+ surge | 28.48 | 3.28 | - | |
MTmax | h | Food effect of lunch | 22.38 | 22.37 | - |
Ef4h | mL | Food effect of dinner | 40.04 | 3.15 | - |
Ef10h | mL | Elimination rate constant for food effect | 97.7 | 4.42 | - |
KFE | 1/h | 0.64 | 8.29 | - | |
- | Additive residual error | 1.28 | - | - |
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Jia, R.; Zhang, F.; Wu, N.; Xu, W.; Gao, H.; Liu, B.; Wang, H. Accelerating Development of Benziamidazole-Class Proton Pump Inhibitors: A Mechanism-Based PK/PD Model to Optimize Study Design with Ilaprazole as a Case Drug. Pharmaceutics 2021, 13, 392. https://doi.org/10.3390/pharmaceutics13030392
Jia R, Zhang F, Wu N, Xu W, Gao H, Liu B, Wang H. Accelerating Development of Benziamidazole-Class Proton Pump Inhibitors: A Mechanism-Based PK/PD Model to Optimize Study Design with Ilaprazole as a Case Drug. Pharmaceutics. 2021; 13(3):392. https://doi.org/10.3390/pharmaceutics13030392
Chicago/Turabian StyleJia, Ranran, Fan Zhang, Ni Wu, Wen Xu, Huitao Gao, Bo Liu, and Hongyun Wang. 2021. "Accelerating Development of Benziamidazole-Class Proton Pump Inhibitors: A Mechanism-Based PK/PD Model to Optimize Study Design with Ilaprazole as a Case Drug" Pharmaceutics 13, no. 3: 392. https://doi.org/10.3390/pharmaceutics13030392
APA StyleJia, R., Zhang, F., Wu, N., Xu, W., Gao, H., Liu, B., & Wang, H. (2021). Accelerating Development of Benziamidazole-Class Proton Pump Inhibitors: A Mechanism-Based PK/PD Model to Optimize Study Design with Ilaprazole as a Case Drug. Pharmaceutics, 13(3), 392. https://doi.org/10.3390/pharmaceutics13030392