Accelerated Repurposing and Drug Development of Pulmonary Hypertension Therapies for COVID-19 Treatment Using an AI-Integrated Biosimulation Platform
Abstract
:1. Introduction
2. Results
2.1. Sensitivity and Convergence Testing
2.2. Simulation Accuracy
2.3. Simulating Distribution to Gut, Lung, and Nasal Epithelium
3. Discussion
4. Materials and Methods
4.1. Overview of BIOiSIM Platform
4.2. Modeling Compound Disposition
4.3. Rapid Repurposing Workflow
4.3.1. Test Dataset
4.3.2. Statistics and Tools
4.3.3. Subjects
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Compound Name | Development | Overview | Source |
---|---|---|---|
Remdesivir | Gilead, Approved by FDA | Antiviral, host factor-targeted. RNA-dependent/RNA polymerase-targeted | [20] |
APN01 | APEIRON Biologics, Phase I | Pilot trial ongoing in China | [21] |
Brilacidin | Innovation Pharmaceuticals, Phase II | Defensin mimetic drug candidate. Has shown antibacterial, anti-inflammatory, and immunomodulatory properties in several clinical trials | [22] |
Hydroxychloroquine | Repurposed, Rejected | Host factor-targeted. Antimalarial drug that affects endosomal function and blocks autophagosome-lysosome fusion | [23] |
Azithromycin | Repurposed | Host factor-targeted. Broad-spectrum antibiotic, blocks autophagosome clearance in human cells | [23] |
Camostat | Repurposed | Host factor-targeted. TMPRSS2 inhibitor | [24] |
Nafamostat | Repurposed | Host factor-targeted. TMPRSS2 inhibitor | [25] |
Favipiravir | Repurposed, Approved in Russia, Japan | Host factor-targeted. RNA-dependent/RNA polymerase-targeted | [26] |
Drug Name | Class | ka | LogP | pKa | Fu,p | B:P | Clearance (L/h/kg) | Kplung | Kpgut |
---|---|---|---|---|---|---|---|---|---|
Lisinopril | ACEi | 0.17 * | −1.115 [49] | 3.17 (acid), 10.21 (base) [49] | 0.99 [49] | 0.71 * | 0.072 [49] | 0.57 | 0.50 |
Captopril | ACEi | N/A | 0.34 [50] | 4.01 (acid), −1.2 [49] | 0.73 [49] | 0.45 * | 0.72 [49] | 0.15 * | 0.15 * |
Spirapril | ACEi | 0.53 [51] | 0 * | 3.62 (acid), 5.2 (base) [49] | 0.314678 * | 0.74 ** | 0.43 [51] | 0.21 * | 0.16 * |
Lacidipine | CCB | 1.7843 * | 5.51 [52] | 19.47 (acid), −6.4 (base) [49] | 0.05 [53] | 0.70 * | 1.23 [49] | 11.72 * | 11.72 * |
Verapamil | CCB | N/A | 3.795 [54] | 9.68 (base) [49] | 0.064 [55] | 0.88 [36,54] | 0.84 [49,54,55] | 3.69 * | 3.69 * |
Drug Name | Formulation | Experimental Setup | Reference |
---|---|---|---|
Lisinopril | 20 mg, oral dose | 20 mg of Lisinopril was given orally for 10 consecutive days. 8 subjects in the study. | [56] |
Captopril | 2.78 mg, 5.67 mg, 11.4 mg, IV dose | 1 mL of intravenous injection at three different dosage levels was administered to 7 healthy subjects. | [57] |
Spirapril | 25 mg, oral dose | 25 mg spirapril p.o. prepared by dissolving 25 mg of lyophilized spirapril in 50 mL tap water was given to the subjects. 16 subjects. | [51] |
Lacidipine | 2 mg, 4 mg, oral dose | Single dose of 2 mg and 4 mg of Lacidipine was administered. The study has a total of 24 subjects (12 male, 12 female) | [58] |
Verapamil | 50 mg, IV dose | 5 subjects received 5 mg verapamil dissolved in 30 mL of saline infused over 5 min. | [55] |
Compounds | Lisinopril | Captopril | Spirapril | Lacidipine | Verapamil | ||||
---|---|---|---|---|---|---|---|---|---|
Output metrics | ROA | Oral | IV | IV | IV | Oral | Oral | Oral | IV |
Dose, mg | 20 | 2.78 | 5.67 | 11.4 | 25 | 2 | 4 | 5 | |
AUC0-t, µg·h/L | Observed | N/A | N/A | N/A | N/A | N/A | 3.66 | 7.66 | N/A |
Calculated | 752.00 | 42.97 | 93.93 | 215.69 | 991.83 | 3.12 | 6.80 | 703.03 | |
Predicted | 823.50 | 49.16 | 92.55 | 212.12 | 977.60 | 3.27 | 8.80 | 494.26 | |
AAFE | 1.10 | 1.14 | 1.01 | 1.02 | 1.01 | 1.05 | 1.29 | 1.42 | |
AFE | 1.10 | 1.14 | 0.99 | 0.98 | 0.99 | 1.05 | 1.29 | 0.70 | |
Cmax, µg/L | Observed | N/A | N/A | N/A | N/A | 430.00 | 1.24 | 3.09 | N/A |
Calculated | 57.40 | 104.64 | 234.55 | 454.71 | 378.00 | 1.17 | 2.87 | 1176.82 | |
Predicted | 53.93 | 105.81 | 183.46 | 497.25 | 196.17 | 1.00 | 2.01 | 1696.96 | |
AAFE | 1.06 | 1.01 | 1.28 | 1.09 | 1.93 | 1.16 | 1.43 | 1.44 | |
AFE | 0.94 | 1.01 | 0.78 | 1.09 | 0.52 | 0.86 | 0.70 | 1.44 | |
Tmax, h | Observed | N/A | N/A | N/A | N/A | 0.90 | 1.13 | 1.25 | N/A |
Calculated | 6.04 | 0.15 | 0.19 | 0.13 | 1.00 | 1.23 | 1.05 | 0.09 | |
Predicted | 6.03 | 0.15 | 0.19 | 0.13 | 1.75 | 1.05 | 1.05 | 0.09 | |
AAFE | 1.00 | 1.00 | 1.00 | 1.00 | 1.75 | 1.17 | 1.00 | 1.00 | |
AFE | 1.00 | 1.00 | 1.00 | 1.00 | 1.75 | 0.86 | 1.00 | 1.00 | |
Statistics | Chi-squared | 2803.13 * | 22.56 | 23.01 | 26.85 | 2.70 | 107.9 * | 182.15 * | 11.57 * |
p-values | >0.50 | >0.50 | >0.50 | >0.50 | <0.001 | >0.50 | >0.50 | 0.36 |
Metrics | Tissue | Lisinopril, 20 mg, oral | Captopril, 2.78 mg, IV | Spirapril, 25 mg, oral | Lacidipine, 2 mg, oral | Verapamil, 50 mg, IV |
---|---|---|---|---|---|---|
AUC0–t, µg·h/L | Lung | 341.24 | 52.36 | 2315.64 | 13.86 | 344.12 |
Gut | 354.03 | 196.74 | 2310.31 | 13.86 | 354.74 | |
Nasal tissue | 196.91 | 1.48 | 207.74 | 31.63 | 360.48 | |
Nasal epithelium | 196.34 | 1.48 | 207.58 | 31.63 | 360.48 | |
Cmax, µg/L | Lung | 34.07 | 15.26 | 7514.65 | 140.24 | 65.26 |
Gut | 33.68 | 103.16 | 3213.00 | 92.77 | 70.37 | |
Nasal tissue | 19.67 | 0.43 | 657.99 | 256.36 | 68.36 | |
Nasal epithelium | 19.67 | 0.43 | 478.23 | 128.78 | 68.35 | |
Tmax, h | Lung | 6.65 | 1.13 | 0.08 | 0.02 | 1.84 |
Gut | 5.68 | 0.57 | 0.13 | 0.03 | 1.30 | |
Nasal tissue | 6.66 | 1.13 | 0.09 | 0.02 | 1.85 | |
Nasal epithelium | 6.69 | 1.17 | 0.11 | 0.05 | 1.89 |
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Chakravarty, K.; Antontsev, V.G.; Khotimchenko, M.; Gupta, N.; Jagarapu, A.; Bundey, Y.; Hou, H.; Maharao, N.; Varshney, J. Accelerated Repurposing and Drug Development of Pulmonary Hypertension Therapies for COVID-19 Treatment Using an AI-Integrated Biosimulation Platform. Molecules 2021, 26, 1912. https://doi.org/10.3390/molecules26071912
Chakravarty K, Antontsev VG, Khotimchenko M, Gupta N, Jagarapu A, Bundey Y, Hou H, Maharao N, Varshney J. Accelerated Repurposing and Drug Development of Pulmonary Hypertension Therapies for COVID-19 Treatment Using an AI-Integrated Biosimulation Platform. Molecules. 2021; 26(7):1912. https://doi.org/10.3390/molecules26071912
Chicago/Turabian StyleChakravarty, Kaushik, Victor G. Antontsev, Maksim Khotimchenko, Nilesh Gupta, Aditya Jagarapu, Yogesh Bundey, Hypatia Hou, Neha Maharao, and Jyotika Varshney. 2021. "Accelerated Repurposing and Drug Development of Pulmonary Hypertension Therapies for COVID-19 Treatment Using an AI-Integrated Biosimulation Platform" Molecules 26, no. 7: 1912. https://doi.org/10.3390/molecules26071912
APA StyleChakravarty, K., Antontsev, V. G., Khotimchenko, M., Gupta, N., Jagarapu, A., Bundey, Y., Hou, H., Maharao, N., & Varshney, J. (2021). Accelerated Repurposing and Drug Development of Pulmonary Hypertension Therapies for COVID-19 Treatment Using an AI-Integrated Biosimulation Platform. Molecules, 26(7), 1912. https://doi.org/10.3390/molecules26071912