Prediction of CYP-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Modeling: A Case Study of Salbutamol and Fluvoxamine
Abstract
:1. Introduction
2. Materials and Methods
2.1. Prediction of Pharmacokinetic and Physicochemical Properties of Salbutamol
2.2. Screening of Potential Drug Interactors with Salbutamol
2.3. PBPK Modeling Development
2.4. PBPK Model Validation
2.5. DDI Simulation between Salbutamol and Fluvoxamine
3. Results and Discussion
3.1. Fluvoxamine as the Perpetrator Drug for Salbutamol DDI Study
3.2. PBPK Model for Salbutamol
3.3. Effect of Different Doses of Fluvoxamine on Salbutamol Pharmacokinetics
3.4. Effect of Different Ages on Salbutamol Pharmacokinetics Co-Administered with Fluvoxamine
3.5. Effect of Comorbidities on Salbutamol Pharmacokinetics Co-Administered with Fluvoxamine
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Physicochemical Properties | Predicted Value | Optimized Value | Reference |
---|---|---|---|
Log P | 1.644 | 1.4 | [18,21,22,23,24] |
Ionization constant (pKa) | 9.98 | 10.3 | |
Molecular Weight (g/mol) | 239.317 | 239.31 | |
Water Solubility (mg/mL) | 15.869 | 9.53 | [22] |
Diff. Coeff. (cm2/s·105) | 0.804 | ND | ND |
Peff (cm/s·104) | 1.331 | 0.815 | Calculated from pkCSM [21] |
BBB penetration | Low | Low | Calculated from SwissADME and pkCSM [21,22] |
Drug | CYP Enzyme | Inhibitor | Substrate | Km | Vmax | CL | Sites of Metabolism |
---|---|---|---|---|---|---|---|
Salbutamol | 1A2 | No (90%) | No (97%) | NS | NS | NS | NS |
2A6 | ND | No (98%) | NS | NS | NS | NS | |
2B6 | ND | No (65%) | NS | NS | NS | NS | |
2C8 | ND | No (92%) | NS | NS | NS | NS | |
2C9 | No (99%) | No (98%) | NS | NS | NS | NS | |
2C19 | ND | Yes (82%) | 30.146 | 157.577 | 73.179 | C7 | |
2D6 | Yes (49%) | Yes (66%) | 37.808 | 2.201 | 0.466 | C17 | |
2E1 | ND | No (91%) | NS | NS | NS | NS | |
3A4 | No (78%) | No (84%) | NS | NS | NS | NS | |
Fluvoxamine | 1A2 | No (51%) | Yes (48%) | 1.821 | 1.500 | 42.835 | C1, C11 |
2A6 | ND | No (82%) | NS | NS | NS | NS | |
2B6 | ND | No (83%) | NS | NS | NS | NS | |
2C8 | ND | No (99%) | NS | NS | NS | NS | |
2C9 | Yes (41%) | No (78%) | NS | NS | NS | NS | |
2C19 | No (95%) | Yes (67%) | 22.656 | 250.097 | 154.542 | C1, C3, C11, C12 | |
2D6 | Yes (70%) | Yes (66%) | 0.674 | 3.937 | 46.721 | C1, C3, C11 | |
2E1 | ND | Yes (78%) | ND | ND | ND | C1, C3, C12 | |
3A4 | Yes (80%) | No (54%) | NS | NS | NS | NS |
Pharmacokinetic Parameters | Observed Value | Estimated Value |
---|---|---|
Fa (%) | 88.82 | 88.079 |
FDp (%) | ND | 87.486 |
F (%) | ND | 29.447 |
Cmax (μg/mL) | 0.01013 | 3.159 × 10−3 |
Tmax (h) | 2.73 | 19.84 |
AUC0–inf (μg*h/mL) | 0.1094 | 0.05235 |
AUC0–t (μg*h/mL) | 0.1094 | 0.04929 |
Cmax liver (μg/mL) | ND | 7.57 × 10−3 |
Compound | Fa (%) | FDp (%) | F (%) | Cmax (μg/mL) | Tmax (h) | AUC0–t (ng.h/mL) | AUC0-inf (ng.h/mL) |
---|---|---|---|---|---|---|---|
Salbutamol baseline | 88.08 | 87.49 | 29.44 | 0.0032 | 19.76 | 52.34 | 49.65 |
Salbutamol 4 mg + fluvoxamine 100 mg | 88.06 | 87.47 | 38.50 | 0.0052 | 7.92 | 78.04 | 74.19 |
Salbutamol 4 mg + fluvoxamine 200 mg | 88.04 | 87.45 | 44.76 | 0.0067 | 7.92 | 100.6 | 95.39 |
Salbutamol 4 mg + fluvoxamine 300 mg | 88.03 | 87.43 | 49.41 | 0.0080 | 8.00 | 120.6 | 113.9 |
Dosing Regimen | Concentration Type | AUC Ratio | DDI Classification | ||||
---|---|---|---|---|---|---|---|
Age | 10 | 30 | 65 | 10 | 30 | 65 | |
Salbutamol with fluvoxamine 100 mg | Cmax | 3.453 | 3.630 | 3.431 | M | M | M |
Liver Unbound | 2.726 | 2.021 | 2.586 | M | M | M | |
Salbutamol with fluvoxamine 200 mg | Cmax | 3.854 | 3.973 | 3.839 | M | M | M |
Liver Unbound | 3.287 | 2.558 | 3.156 | M | M | M | |
Salbutamol with fluvoxamine 300 mg | Cmax | 4.022 | 4.111 | 4.011 | M | M | M |
Liver Unbound | 3.567 | 2.903 | 3.456 | M | M | M |
Dosing Regimen | Concentration Type | AUC Ratio | DDI Classification | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Physiological Status | Healthy | OW | Obese | MildRI | MRI | SRI | Healthy | OW | Obese | MildRI | MRI | SRI | |
Salbutamol 4 mg + fluvoxamine 100 mg | Cmax | 3.630 | 3.420 | 3.413 | 3.423 | 3.423 | 3.423 | M | M | M | M | M | M |
Liver Unbound | 2.021 | 2.501 | 2.451 | 2.511 | 2.511 | 2.511 | M | M | M | M | M | M | |
Salbutamol 4 mg + fluvoxamine 200 mg | Cmax | 3.973 | 3.831 | 3.827 | 3.832 | 3.832 | 3.832 | M | M | M | M | M | M |
Liver Unbound | 2.558 | 3.075 | 3.031 | 3.089 | 3.089 | 3.089 | M | M | M | M | M | M | |
Salbutamol 4 mg + fluvoxamine 300 mg | Cmax | 4.111 | 4.005 | 4.001 | 4.006 | 4.006 | 4.006 | M | M | M | M | M | M |
Liver Unbound | 2.903 | 3.385 | 3.341 | 3.396 | 3.396 | 3.396 | M | M | M | M | M | M |
Dosing Regimen | Concentration Type | AUC Ratio | DDI Classification | ||
---|---|---|---|---|---|
Age | Female | Pregnant | Female | Pregnant | |
Salbutamol 4 mg + fluvoxamine 100 mg | Cmax | 3.426 | 3.426 | M | M |
Liver Unbound | 2.530 | 2.540 | M | M | |
Salbutamol 4 mg + fluvoxamine 200 mg | Cmax | 3.835 | 3.835 | M | M |
Liver Unbound | 3.112 | 3.117 | M | M | |
Salbutamol 4 mg + fluvoxamine 300 mg | Cmax | 4.007 | 4.007 | M | M |
Liver Unbound | 3.415 | 3.420 | M | M |
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Marques, L.; Vale, N. Prediction of CYP-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Modeling: A Case Study of Salbutamol and Fluvoxamine. Pharmaceutics 2023, 15, 1586. https://doi.org/10.3390/pharmaceutics15061586
Marques L, Vale N. Prediction of CYP-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Modeling: A Case Study of Salbutamol and Fluvoxamine. Pharmaceutics. 2023; 15(6):1586. https://doi.org/10.3390/pharmaceutics15061586
Chicago/Turabian StyleMarques, Lara, and Nuno Vale. 2023. "Prediction of CYP-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Modeling: A Case Study of Salbutamol and Fluvoxamine" Pharmaceutics 15, no. 6: 1586. https://doi.org/10.3390/pharmaceutics15061586
APA StyleMarques, L., & Vale, N. (2023). Prediction of CYP-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Modeling: A Case Study of Salbutamol and Fluvoxamine. Pharmaceutics, 15(6), 1586. https://doi.org/10.3390/pharmaceutics15061586