Triplet analysis: Quantifying ivacaftor, tezacaftor, and elexacaftor in plasma with mass spectrometry

Ravikanth Inturi; Srikanth Inturi; David Raju Medepalli; Venkata Basaveswara Rao Mandava

doi:10.7324/JAPS.2024.182963

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Abstract

A novel and highly precise method were developed and rigorously validated for quantifying ivacaftor (IVA), tezacaftor (TEZ), and elexacaftor (ELX) in human plasma. This method leverages multiple reaction-monitoring mass spectrometry for its analytical approach. During the validation process, the method demonstrated its robustness across a wide concentration range: 0.151 to 40.382 ng/ml for ELX, 0.101 to 30.010 ng/ml for IVA, and 20.187 to 6,026.032 ng/ml for TEZ in human plasma. Importantly, this method exhibited exceptional accuracy and reproducibility even at lower concentrations. The mobile phase employed in this analysis consisted of methanol and 0.1% formic acid at a ratio of 85:15 (v/v), with a flow rate set at 1.0 ml/minute. Additionally, linear correlations were established within the human plasma for ELX (R2=0.9983), IVA (R2=0.9992), and TEZ (R2=0.9989). In conclusion, this newly developed method is dependable and precise for the accurate quantification of IVA, TEZ, and ELX, especially when dealing with lower concentrations in human plasma analysis.

Keyword: Ivacaftor tezacaftor elexacaftor lumacaftor LC-MS/MS validation

Citation:

Inturi R, Inturi S, Medepalli DR, Mandava VBR. Triplet analysis: Quantifying ivacaftor, tezacaftor, and elexacaftor in plasma with mass spectrometry. J Appl Pharm Sci. 2024. Online First. http://doi.org/10.7324/JAPS.2024.182

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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1. Taylor-Cousar JL, Munck A, McKone EF, van der Ent CK, Moeller A, Simard C, et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med. 2017;377(21):2013-23. https://doi.org/10.1056/NEJMoa1709846
2. Schneider EK, Reyes-Ortega F, Li J, Velkov T. Can cystic fibrosis patients finally catch a breath with lumacaftor/ivacaftor? Clin Pharmacol Ther. 2017;101(1):130-41. https://doi.org/10.1002/cpt.548
3. Schneider-Futschik EK. Beyond cystic fibrosis transmembrane conductance regulator therapy: a perspective on gene therapy and small molecule treatment for cystic fibrosis. Gene Ther. 2019;26(9):354-62. https://doi.org/10.1038/s41434-019-0092-5
4. Qiu F, Habgood M, Schneider-Futschik EK. The balance between the safety of mother, fetus, and newborn undergoing cystic fibrosis transmembrane conductance regulator treatments during pregnancy. ACS Pharmacol Transl Sci. 2020;3(5):835-43. https://doi.org/10.1021/acsptsci.0c00098
5. Rowe SM, Daines C, Ringshausen FC, Kerem E, Wilson J, Tullis E, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017;377(21):2024-35. https://doi.org/10.1056/NEJMoa1709847
6. Rowe SM, McColley SA, Rietschel E, Li X, Bell SC, Konstan MW, et al. VX09-809-102 study group. Lumacaftor/Ivacaftor treatment of patients with cystic fibrosis heterozygous for F508del-CFTR. Ann Am Thorac Soc. 2017;14(2):213-9. https://doi.org/10.1513/AnnalsATS.201609-689OC
7. Donaldson SH, Pilewski JM, Griese M, Cooke J, Viswanathan L, Tullis E, et al. VX11-661-101 study group. Tezacaftor/ivacaftor in subjects with cystic fibrosis and F508del/F508del-CFTR or F508del/ G551D-CFTR. Am J Respir Crit Care Med. 2018;197(2):214-24. https://doi.org/10.1164/rccm.201704-0717OC
8. Paulin O, Schneider-Futschik E. Treatment challenges associated with drug-drug interactions in cystic fibrosis, in optimizing pharmaceutical treatment in cystic fibrosis. Karup, Denmark: ECFS.
9. Keating D, Marigowda G, Burr L, Daines C, Mall MA, McKone EF, et al. VX16-445-001 study group. VX-445-Tezacaftor-Ivacaftor in patients with cystic fibrosis and one or two Phe508del Alleles. N Engl J Med. 2018;379(17):1612-20. https://doi.org/10.1056/NEJMoa1807120
10. Ghelani DP, Schneider-Futschik EK. Emerging cystic fibrosis transmembrane conductance regulator modulators as new drugs for cystic fibrosis: a portrait of in vitro pharmacology and clinical translation. ACS Pharmacol Transl Sci. 2019;3(1):4-10. https://doi.org/10.1021/acsptsci.9b00060
11. Middleton PG, Mall MA, D?evínek P, Lands LC, McKone EF, Polineni D, et al. VX17-445-102 study group. Elexacaftor-tezacaftorivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. 2019;381(19):1809-19. https://doi.org/10.1056/NEJMoa1908639
12. Tan M, Reyes-Ortega F, Schneider-Futschik E. Successes and challenges: inhaled treatment approaches using magnetic nanoparticles in cystic fibrosis. Magnetochemistry. 2020;6:25. https://doi.org/10.3390/magnetochemistry6020025
13. Assessment Report. Committee for medicinal products for human use. Orkambi (Ivacaftor/Lumacaftor). London, UK: European Medicines Agency; 2015. Report No. EMEA/H/C/003954/0000
14. Schneider EK, Reyes-Ortega F, Wilson JW, Kotsimbos T, Keating D, Li J, et al. Development of HPLC and LC-MS/MS methods for the analysis of ivacaftor, its major metabolites and lumacaftor in plasma and sputum of cystic fibrosis patients treated with ORKAMBI or KALYDECO. J Chromatogr B Analyt Technol Biomed Life Sci. 2016;1038:57-62. https://doi.org/10.1016/j.jchromb.2016.10.026
15. Schneider EK, Reyes-Ortega F, Li J, Velkov T. Optimized LC-MS/ MS method for the high-throughput analysis of clinical samples of ivacaftor, its major metabolites, and lumacaftor in biological fluids of cystic fibrosis patients. J Vis Exp. 2017;128:56084. https://doi.org/10.3791/56084-v
16. Hanafin PO, Sermet-Gaudelus I, Griese M, Kappler M, Ellemunter H, Schwarz C, et al. Insights into patient variability during ivacaftor-lumacaftor therapy in cystic fibrosis. Front Pharmacol. 2021;12:577263. https://doi.org/10.3389/fphar.2021.577263
17. Schneider E, Hanafin P, Rao G. A retrospective observational study: bidirectional pharmacokinetic interactions between ivacaftorlumacaftor in cystic fibrosis. Eur Respir J. 2020;56:362 https://doi.org/10.1183/13993003.congress-2020.362
18. Masson A, Schneider-Futschik EK, Baatallah N, Nguyen-Khoa T, Girodon E, Hatton A, et al. Predictive factors for lumacaftor/ ivacaftor clinical response. J Cystic Fibrosis. 2019;18(3):368-74. https://doi.org/10.1016/j.jcf.2018.12.011
19. Lim A, Balouch F, Cheney J, Lewindon P, Roberts J, Schneider- Futschik E, et al. Orkambi in patients with cystic fibrosis and severe liver disease. Annual Scientific Meeting, Transplantation Society of Australia and New Zealand, Melbourne, Victoria, Australia, Abstract No. TP 092, 2020.
20. Kuzyk MA, Parker CE, Domanski D, Borchers CH. Development of MRM-based assays for the absolute quantitation of plasma proteins. Methods Mol Biol. 2013;1023:53-82. https://doi.org/10.1007/978-1-4614-7209-4_4
21. Hammad LA, Saleh MM, Novotny MV, Mechref Y. Multiplereaction monitoring liquid chromatography mass spectrometry for monosaccharide compositional analysis of glycoproteins. J Am Soc Mass Spectrom. 2009;20(6):1224-34. https://doi.org/10.1016/j.jasms.2009.02.022
22. Quon BS, Dai DL, Hollander Z, Ng RT, Tebbutt SJ, Man SF, et al. Discovery of novel plasma protein biomarkers to predict imminent cystic fibrosis pulmonary exacerbations using multiple reaction monitoring mass spectrometry. Thorax. 2016;71(3):216-22. https://doi.org/10.1136/thoraxjnl-2014-206710
23. Roberts JM, Dai DLY, Hollander Z, Ng RT, Tebbutt SJ, Wilcox PG, et al. Multiple reaction monitoring mass spectrometry to identify novel plasma protein biomarkers of treatment response in cystic fibrosis pulmonary exacerbations. J Cyst Fibros. 2018;17(3):333-40. https://doi.org/10.1016/j.jcf.2017.10.013
24. Guidance for Industry. Bioanalytical method validation center for drug evaluation and research. Silver Spring, MD: U.S. Department of Health and Human Services, Food and Drug Administration, 2001.
25. Su Q, Li J, Ji X, Li J, Zhou T, Lu W, et al. An LC-MS/MS method for the quantitation of cabozantinib in rat plasma: application to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed LifeSci. 2015;985:119-23. https://doi.org/10.1016/j.jchromb.2015.01.024
26. Singh N, Bansal P, Maithani M, Chauhan Y. Development and validation of a novel stability-indicating RP-HPLC method for simultaneous determination of tezacaftor and ivacaftor in fixed dose combination. J Chromatogr Sci. 2020;58(4):346-54. https://doi.org/10.1093/chromsci/bmz120

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1. Taylor-Cousar JL, Munck A, McKone EF, van der Ent CK, Moeller A, Simard C, et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med. 2017;377(21):2013-23. https://doi.org/10.1056/NEJMoa1709846

2. Schneider EK, Reyes-Ortega F, Li J, Velkov T. Can cystic fibrosis patients finally catch a breath with lumacaftor/ivacaftor? Clin Pharmacol Ther. 2017;101(1):130-41. https://doi.org/10.1002/cpt.548

3. Schneider-Futschik EK. Beyond cystic fibrosis transmembrane conductance regulator therapy: a perspective on gene therapy and small molecule treatment for cystic fibrosis. Gene Ther. 2019;26(9):354-62. https://doi.org/10.1038/s41434-019-0092-5

4. Qiu F, Habgood M, Schneider-Futschik EK. The balance between the safety of mother, fetus, and newborn undergoing cystic fibrosis transmembrane conductance regulator treatments during pregnancy. ACS Pharmacol Transl Sci. 2020;3(5):835-43. https://doi.org/10.1021/acsptsci.0c00098

5. Rowe SM, Daines C, Ringshausen FC, Kerem E, Wilson J, Tullis E, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017;377(21):2024-35. https://doi.org/10.1056/NEJMoa1709847

6. Rowe SM, McColley SA, Rietschel E, Li X, Bell SC, Konstan MW, et al. VX09-809-102 study group. Lumacaftor/Ivacaftor treatment of patients with cystic fibrosis heterozygous for F508del-CFTR. Ann Am Thorac Soc. 2017;14(2):213-9. https://doi.org/10.1513/AnnalsATS.201609-689OC

7. Donaldson SH, Pilewski JM, Griese M, Cooke J, Viswanathan L, Tullis E, et al. VX11-661-101 study group. Tezacaftor/ivacaftor in subjects with cystic fibrosis and F508del/F508del-CFTR or F508del/ G551D-CFTR. Am J Respir Crit Care Med. 2018;197(2):214-24. https://doi.org/10.1164/rccm.201704-0717OC

8. Paulin O, Schneider-Futschik E. Treatment challenges associated with drug-drug interactions in cystic fibrosis, in optimizing pharmaceutical treatment in cystic fibrosis. Karup, Denmark: ECFS.

9. Keating D, Marigowda G, Burr L, Daines C, Mall MA, McKone EF, et al. VX16-445-001 study group. VX-445-Tezacaftor-Ivacaftor in patients with cystic fibrosis and one or two Phe508del Alleles. N Engl J Med. 2018;379(17):1612-20. https://doi.org/10.1056/NEJMoa1807120

10. Ghelani DP, Schneider-Futschik EK. Emerging cystic fibrosis transmembrane conductance regulator modulators as new drugs for cystic fibrosis: a portrait of in vitro pharmacology and clinical translation. ACS Pharmacol Transl Sci. 2019;3(1):4-10. https://doi.org/10.1021/acsptsci.9b00060

11. Middleton PG, Mall MA, D?evínek P, Lands LC, McKone EF, Polineni D, et al. VX17-445-102 study group. Elexacaftor-tezacaftorivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. 2019;381(19):1809-19. https://doi.org/10.1056/NEJMoa1908639

12. Tan M, Reyes-Ortega F, Schneider-Futschik E. Successes and challenges: inhaled treatment approaches using magnetic nanoparticles in cystic fibrosis. Magnetochemistry. 2020;6:25. https://doi.org/10.3390/magnetochemistry6020025

13. Assessment Report. Committee for medicinal products for human use. Orkambi (Ivacaftor/Lumacaftor). London, UK: European Medicines Agency; 2015. Report No. EMEA/H/C/003954/0000

14. Schneider EK, Reyes-Ortega F, Wilson JW, Kotsimbos T, Keating D, Li J, et al. Development of HPLC and LC-MS/MS methods for the analysis of ivacaftor, its major metabolites and lumacaftor in plasma and sputum of cystic fibrosis patients treated with ORKAMBI or KALYDECO. J Chromatogr B Analyt Technol Biomed Life Sci. 2016;1038:57-62. https://doi.org/10.1016/j.jchromb.2016.10.026

15. Schneider EK, Reyes-Ortega F, Li J, Velkov T. Optimized LC-MS/ MS method for the high-throughput analysis of clinical samples of ivacaftor, its major metabolites, and lumacaftor in biological fluids of cystic fibrosis patients. J Vis Exp. 2017;128:56084. https://doi.org/10.3791/56084-v

16. Hanafin PO, Sermet-Gaudelus I, Griese M, Kappler M, Ellemunter H, Schwarz C, et al. Insights into patient variability during ivacaftor-lumacaftor therapy in cystic fibrosis. Front Pharmacol. 2021;12:577263. https://doi.org/10.3389/fphar.2021.577263

17. Schneider E, Hanafin P, Rao G. A retrospective observational study: bidirectional pharmacokinetic interactions between ivacaftorlumacaftor in cystic fibrosis. Eur Respir J. 2020;56:362 https://doi.org/10.1183/13993003.congress-2020.362

18. Masson A, Schneider-Futschik EK, Baatallah N, Nguyen-Khoa T, Girodon E, Hatton A, et al. Predictive factors for lumacaftor/ ivacaftor clinical response. J Cystic Fibrosis. 2019;18(3):368-74. https://doi.org/10.1016/j.jcf.2018.12.011

19. Lim A, Balouch F, Cheney J, Lewindon P, Roberts J, Schneider- Futschik E, et al. Orkambi in patients with cystic fibrosis and severe liver disease. Annual Scientific Meeting, Transplantation Society of Australia and New Zealand, Melbourne, Victoria, Australia, Abstract No. TP 092, 2020.

20. Kuzyk MA, Parker CE, Domanski D, Borchers CH. Development of MRM-based assays for the absolute quantitation of plasma proteins. Methods Mol Biol. 2013;1023:53-82. https://doi.org/10.1007/978-1-4614-7209-4_4

21. Hammad LA, Saleh MM, Novotny MV, Mechref Y. Multiplereaction monitoring liquid chromatography mass spectrometry for monosaccharide compositional analysis of glycoproteins. J Am Soc Mass Spectrom. 2009;20(6):1224-34. https://doi.org/10.1016/j.jasms.2009.02.022

22. Quon BS, Dai DL, Hollander Z, Ng RT, Tebbutt SJ, Man SF, et al. Discovery of novel plasma protein biomarkers to predict imminent cystic fibrosis pulmonary exacerbations using multiple reaction monitoring mass spectrometry. Thorax. 2016;71(3):216-22. https://doi.org/10.1136/thoraxjnl-2014-206710

23. Roberts JM, Dai DLY, Hollander Z, Ng RT, Tebbutt SJ, Wilcox PG, et al. Multiple reaction monitoring mass spectrometry to identify novel plasma protein biomarkers of treatment response in cystic fibrosis pulmonary exacerbations. J Cyst Fibros. 2018;17(3):333-40. https://doi.org/10.1016/j.jcf.2017.10.013

24. Guidance for Industry. Bioanalytical method validation center for drug evaluation and research. Silver Spring, MD: U.S. Department of Health and Human Services, Food and Drug Administration, 2001.

25. Su Q, Li J, Ji X, Li J, Zhou T, Lu W, et al. An LC-MS/MS method for the quantitation of cabozantinib in rat plasma: application to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed LifeSci. 2015;985:119-23. https://doi.org/10.1016/j.jchromb.2015.01.024

26. Singh N, Bansal P, Maithani M, Chauhan Y. Development and validation of a novel stability-indicating RP-HPLC method for simultaneous determination of tezacaftor and ivacaftor in fixed dose combination. J Chromatogr Sci. 2020;58(4):346-54. https://doi.org/10.1093/chromsci/bmz120