{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T17:47:16Z","timestamp":1792432036043,"version":"4.5.0"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"26","license":[{"start":{"date-parts":[[2024,8,28]],"date-time":"2024-08-28T00:00:00Z","timestamp":1724803200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,8,28]],"date-time":"2024-08-28T00:00:00Z","timestamp":1724803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004047","name":"Karolinska Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004047","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Anal Bioanal Chem"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The four cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators, ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have revolutionised the treatment of CF by direct action on the protein target behind the disease\u2019s development. The aim was to develop and validate a quantification method for these CFTR modulators in plasma and breast milk to better understand inter-patient variability in pharmacokinetics and treatment outcome, including the risk of adverse drug reactions. The ability to monitor CFTR modulators in breast milk enables the estimation of the exposure of breastfed infant, with a potential concern for CFTR modulator-induced liver injury. The analysis was performed on a Thermo Vanquish Flex Binary UHPLC system coupled to a high-resolution mass spectrometer (HRMS), Thermo Q Exactive. The analytes were detected using positive electrospray ionisation in full scan mode. After sample preparation by protein precipitation, the supernatant was injected onto the LC system and the analytes were separated using a Zorbax SB-C18 Rapid Res HPLC column (3.5\u00a0\u00b5m, 4.6\u2009\u00d7\u200975\u00a0mm). This is the first published method for CFTR modulators in breast milk. The validated quantification range for ivacaftor is 0.0050\u201310\u00a0\u00b5g\/mL with a coefficient of variation\u2009&lt;\u20096% and a mean accuracy of 97\u2013106%; for lumacaftor, tezacaftor, and elexacaftor, the validated quantification range is 0.050\u2013100\u00a0\u00b5g\/mL with a coefficient of variation\u2009&lt;\u20098% and a mean accuracy 93\u2013106%. A simple and sensitive quantification method for CFTR modulators has been developed and used for routine analysis of human plasma and breast milk samples since 2022.<\/jats:p>\n                <jats:p><jats:bold>Graphical Abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s00216-024-05496-2","type":"journal-article","created":{"date-parts":[[2024,8,28]],"date-time":"2024-08-28T11:02:20Z","timestamp":1724842940000},"page":"5565-5577","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Development and clinical implementation of an LC-HRMS method for ivacaftor, lumacaftor, tezacaftor and elexacaftor in human plasma and breast milk"],"prefix":"10.1007","volume":"416","author":[{"given":"Anna B.","family":"Hansson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hjalmar","family":"Wadstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Eliasson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahasin","family":"Al Shakirchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"de Monestrol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Barclay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,28]]},"reference":[{"key":"5496_CR1","doi-asserted-by":"crossref","unstructured":"Cholon DM, Quinney NL, Fulcher ML, Esther CR, Jr., Das J, Dokholyan NV, et al. Potentiator ivacaftor abrogates pharmacological correction of DeltaF508 CFTR in cystic fibrosis. Sci Transl Med. 2014;6(246):246ra96.","DOI":"10.1126\/scitranslmed.3008680"},{"issue":"19","key":"5496_CR2","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1056\/NEJMoa1908639","volume":"381","author":"PG Middleton","year":"2019","unstructured":"Middleton PG, Mall MA, Drevinek P, Lands LC, McKone EF, Polineni D, et al. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. 2019;381(19):1809\u201319.","journal-title":"N Engl J Med"},{"issue":"3","key":"5496_CR3","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/j.jcf.2020.12.011","volume":"20","author":"KE O\u2019Connor","year":"2021","unstructured":"O\u2019Connor KE, Goodwin DL, NeSmith A, Garcia B, Mingora C, Ladores SL, et al. Elexacafator\/tezacaftor\/ivacaftor resolves subfertility in females with CF: a two center case series. J Cyst Fibros. 2021;20(3):399\u2013401.","journal-title":"J Cyst Fibros"},{"issue":"2","key":"5496_CR4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1183\/13993003.01208-2019","volume":"55","author":"PG Middleton","year":"2020","unstructured":"Middleton PG, Gade EJ, Aguilera C, MacKillop L, Button BM, Coleman C, et al. ERS\/TSANZ Task Force Statement on the management of reproduction and pregnancy in women with airways diseases. Eur Respir J. 2020;55(2):1\u201324.","journal-title":"Eur Respir J"},{"issue":"4","key":"5496_CR5","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1016\/j.jcf.2021.12.004","volume":"21","author":"B Collins","year":"2022","unstructured":"Collins B, Fortner C, Cotey A, Esther CRJ, Trimble A. Drug exposure to infants born to mothers taking elexacaftor, tezacaftor, and ivacaftor. J Cyst Fibros. 2022;21(4):725\u20137.","journal-title":"J Cyst Fibros"},{"issue":"6","key":"5496_CR6","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1016\/j.jcf.2018.05.009","volume":"17","author":"A Trimble","year":"2018","unstructured":"Trimble A, McKinzie C, Terrell M, Stringer E, Esther CR Jr. Measured fetal and neonatal exposure to lumacaftor and ivacaftor during pregnancy and while breastfeeding. J Cyst Fibros. 2018;17(6):779\u201382.","journal-title":"J Cyst Fibros"},{"issue":"6","key":"5496_CR7","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1016\/j.jcf.2022.10.004","volume":"21","author":"R Jain","year":"2022","unstructured":"Jain R, Wolf A, Molad M, Taylor-Cousar J, Esther CR Jr, Shteinberg M. Congenital bilateral cataracts in newborns exposed to elexacaftor-tezacaftor-ivacaftor in utero and while breast feeding. J Cyst Fibros. 2022;21(6):1074\u20136.","journal-title":"J Cyst Fibros"},{"key":"5496_CR8","unstructured":"Summary of product charateristics (SmPC) Kalydeco, EMEA\/H\/C\/002494 [Internet]. European Medicines Agency (EMA) Amsterdam. 2012. Available from: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/kalydeco. Accessed 23 Oct 2023."},{"key":"5496_CR9","unstructured":"Summary of product charateristics (SMPC) Kaftrio, EMEA\/H\/C\/005269 [Internet]. European Medicines Agency (EMA) Amsterdam. 2020. Available from: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/kaftrio. Accessed 23 Oct 2023."},{"key":"5496_CR10","unstructured":"Summary of product charateristics (SmPC) Symkevi, EMEA\/H\/C\/004682 [Internet]. European Medicines Agency (EMA) Amsterdam. 2018. Available from: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/symkevi. 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Simultaneous quantification of ivacaftor, tezacaftor, and elexacaftor in cystic fibrosis patients\u2019 plasma by a novel LC-MS\/MS method. Biomedicines. 2023;11(2):1\u201311.","journal-title":"Biomedicines"},{"issue":"5","key":"5496_CR16","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1021\/acsptsci.0c00103","volume":"3","author":"F Reyes-Ortega","year":"2020","unstructured":"Reyes-Ortega F, Qiu F, Schneider-Futschik EK. Multiple reaction monitoring mass spectrometry for the drug monitoring of ivacaftor, tezacaftor, and elexacaftor treatment response in cystic fibrosis: a high-throughput method. ACS Pharmacol Transl Sci. 2020;3(5):987\u201396.","journal-title":"ACS Pharmacol Transl Sci"},{"key":"5496_CR17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jchromb.2022.123518","volume":"1213","author":"KJ Ryan","year":"2022","unstructured":"Ryan KJ, Guimbellot JS, Dowell AE, Reed-Walker KD, Kerstner-Wood CD, Anderson JD, et al. Quantitation of cystic fibrosis triple combination therapy, elexacaftor\/tezacaftor\/ivacaftor, in human plasma and cellular lysate. J Chromatogr B Analyt Technol Biomed Life Sci. 2022;1213:1\u201311.","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci"},{"key":"5496_CR18","first-page":"1","volume":"128","author":"EK Schneider","year":"2017","unstructured":"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;128:1\u20137.","journal-title":"J Vis Exp"},{"key":"5496_CR19","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.jchromb.2016.10.026","volume":"1038","author":"EK Schneider","year":"2016","unstructured":"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\u201362.","journal-title":"J Chromatogr B Analyt Technol Biomed Life Sci"},{"key":"5496_CR20","doi-asserted-by":"crossref","unstructured":"Vonk SEM, van der Meer-Vos M, Bos LDJ, Neerincx AH, Majoor CJ, Maitland-van der Zee AH, et al. Quantitative method for the analysis of ivacaftor, hydroxymethyl ivacaftor, ivacaftor carboxylate, lumacaftor, and tezacaftor in plasma and sputum using liquid chromatography with tandem mass spectrometry and its clinical applicability. 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Accessed 13 Dec 2023."}],"container-title":["Analytical and Bioanalytical Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00216-024-05496-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00216-024-05496-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00216-024-05496-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T06:05:06Z","timestamp":1729490706000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00216-024-05496-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,28]]},"references-count":27,"journal-issue":{"issue":"26","published-print":{"date-parts":[[2024,11]]}},"alternative-id":["5496"],"URL":"https:\/\/doi.org\/10.1007\/s00216-024-05496-2","relation":{},"ISSN":["1618-2642","1618-2650"],"issn-type":[{"value":"1618-2642","type":"print"},{"value":"1618-2650","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,28]]},"assertion":[{"value":"11 June 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 July 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 July 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 August 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"No ethical permit was needed since the method validation was based on eight anonymised leftover plasma samples. This is in agreement with legislation: Biobankslag (2023:38) Svensk f\u00f6rfattningssamling 2023:2023:38 \u2013 Riksdagen, and the Swedish Biobank.Between July 2022 and September 2023, approximately 80 clinical patient samples (plasma and breast milk) were analysed in a therapeutic drug monitoring context at the Medical Unit for Clinical Pharmacology, Karolinska University Hospital, Sweden, according to legislation H\u00e4lso- och sjukv\u00e5rdslagen (2017:30). The Therapeutic Drug Monitoring Laboratory, at the Medical Unit for Clinical Pharmacology, is accredited according to ISO 15189:2022 by SWEDAC, the Swedish accreditation body. No concentrations or other results were presented for these samples but only as production statistics to demonstrate the applicability of the method and its clinical demand.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The authors declare no conflicts of interest.Isabelle de Monestrol is principal investigator for pharmaceutical studies, has grants for non-pharmaceutical study, and has been member of steering committees and lecturer, all by receiving payment to institution by Vertex.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}