{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T13:57:42Z","timestamp":1768744662810,"version":"3.49.0"},"reference-count":23,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T00:00:00Z","timestamp":1733356800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015362","name":"Amicus Therapeutics","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015362","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Nuventra, LLC"},{"name":"CRS Clinical Research Services Kiel GmbH"},{"DOI":"10.13039\/100015362","name":"Amicus Therapeutics","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015362","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015362","name":"Amicus Therapeutics","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015362","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Nuventra, LLC"},{"DOI":"10.13039\/100005614","name":"Biogen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005614","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015362","name":"Amicus Therapeutics","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015362","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Fabry disease (FD) is an X-linked lysosomal disorder leading to multiorgan dysfunction, including renal impairment and the risk of significant accumulation for renally excreted drugs. Migalastat, an approved therapy in FD patients with amenable variants, is primarily eliminated in urine; however, its use had not been studied in patients with end-stage renal disease (ESRD) receiving dialysis therapy. This study investigated the pharmacokinetics (PK), dialyzability, and tolerability of 123 mg migalastat in non-FD subjects with ESRD on stable hemodialysis\/hemodiafiltration (EudraCT 2018-003684-57). Results were analyzed by population PK and physiologically based PK (PBPK) modeling and intended to propose dose regimens resulting in negligible migalastat trough levels in plasma and comparable concentrations above the threshold in target tissues in FD patients with ESRD.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Subjects with ESRD received 123 mg migalastat 24 hours before dialysis and, following an 8-day washout, immediately before dialysis. Matched controls with normal renal function (NRF) received migalastat 123 mg. Migalastat concentrations were measured in plasma, urine, and dialysate, and modeled to select regimens providing similar disposition to NRF.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Migalastat was extracted by hemodialysis\/hemodiafiltration (74%\/72%). PBPK modeling predicted that 123 mg every other week (QOW) with regular dialysis 2\u20133 times weekly in ESRD subjects produced: a fraction of time above EC<jats:sub>50<\/jats:sub> similar to FD patients with NRF; adequate C<jats:sub>max<\/jats:sub> for intracellular trafficking of mutant \u03b1-galactosidase A to the lysosome; and C<jats:sub>trough<\/jats:sub> levels near the lower limit of quantification (LLOQ) similar to NRF subjects receiving 123 mg every other day. Migalastat 82 mg weekly produced a greater fraction of time above EC<jats:sub>50<\/jats:sub> and longer duration of concentrations above the LLOQ, potentially resulting in accumulation in tissues.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Migalastat was well extracted by hemodialysis\/hemodiafiltration. Migalastat 123 mg QOW is the proposed dose regimen for further evaluation in FD patients with ESRD, which could inform expansion of treatment options.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec005\">\n<jats:title>Trial registration<\/jats:title>\n<jats:p>Trial registration: EU Clinical Trials Register, EudraCT number <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/eudract.ema.europa.eu\/\" xlink:type=\"simple\">2018-003684-57<\/jats:ext-link>.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0314030","type":"journal-article","created":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T19:00:36Z","timestamp":1733425236000},"page":"e0314030","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pharmacokinetic evaluation of single-dose migalastat in non-Fabry disease subjects with ESRD receiving dialysis treatment, and use of modeling to select dose regimens in Fabry disease subjects with ESRD receiving dialysis treatment"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5426-8171","authenticated-orcid":true,"given":"Franklin K.","family":"Johnson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shirley","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ginny","family":"Schmith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hadis","family":"Williams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasmine","family":"Rutecki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atef","family":"Halabi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thorsten","family":"Feldkamp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Sileno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,12,5]]},"reference":[{"key":"pone.0314030.ref001","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/1750-1172-5-30","article-title":"Fabry disease","volume":"5","author":"DP Germain","year":"2010","journal-title":"Orphanet J Rare Dis"},{"issue":"3","key":"pone.0314030.ref002","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.ymgme.2017.09.004","article-title":"Contribution of inflammatory pathways to Fabry disease pathogenesis","volume":"122","author":"P Rozenfeld","year":"2017","journal-title":"Mol Genet Metab"},{"issue":"4","key":"pone.0314030.ref003","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1002\/cpdd.149","article-title":"An open-label study to determine the pharmacokinetics and safety of migalastat HCl in subjects with impaired renal function and healthy subjects with normal renal function","volume":"4","author":"FK Johnson","year":"2015","journal-title":"Clin Pharmacol Drug Dev"},{"issue":"267","key":"pone.0314030.ref004","doi-asserted-by":"crossref","first-page":"4179","DOI":"10.1046\/j.1432-1327.2000.01457.x","article-title":"In vitro inhibition and intracellular enhancement of lysosomal \u03b1- galactosidase A activity in Fabry lymphoblasts by 1- deoxygalactonojirimycin and its derivatives","volume":"13","author":"IS Asano N","year":"2000","journal-title":"Eur J Biochem"},{"key":"pone.0314030.ref005","unstructured":"Amicus Therapeutics US, Inc. GALAFOLD\u00ae (migalastat) prescribing information. 2023 [21 December 2023]. Available from: https:\/\/amicusrx.com\/pi\/galafold.pdf."},{"key":"pone.0314030.ref006","unstructured":"Amicus Therapeutics Europe Limited. Galafold summary of product characteristics (SmPC). 2022 [21 December 2023]. Available from: https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/galafold-epar-product-information_en.pdf."},{"issue":"4","key":"pone.0314030.ref007","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1038\/gim.2016.122","article-title":"The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat","volume":"19","author":"ER Benjamin","year":"2017","journal-title":"Genet Med"},{"issue":"4","key":"pone.0314030.ref008","doi-asserted-by":"crossref","first-page":"107714","DOI":"10.1016\/j.ymgme.2023.107714","article-title":"Prevalence of Fabry disease in patients with chronic kidney disease: A systematic review and meta-analysis","volume":"140","author":"D Linares","year":"2023","journal-title":"Mol Genet Metab"},{"issue":"1","key":"pone.0314030.ref009","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1177\/009127000004000103","article-title":"Clinical pharmacology studies in patients with renal impairment: past experience and regulatory perspectives","volume":"40","author":"S Ibrahim","year":"2000","journal-title":"J Clin Pharmacol"},{"issue":"2","key":"pone.0314030.ref010","article-title":"Hemodiafiltration: Technical and Medical Insights","volume":"10","author":"T Lang","year":"2023","journal-title":"Bioengineering (Basel)"},{"issue":"suppl_3","key":"pone.0314030.ref011","doi-asserted-by":"crossref","first-page":"iii6","DOI":"10.1093\/ndt\/gfy179","article-title":"Large uremic toxins: an unsolved problem in end-stage kidney disease","volume":"33","author":"MJ Wolley","year":"2018","journal-title":"Nephrol Dial Transplant"},{"issue":"3","key":"pone.0314030.ref012","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1093\/ndt\/gfz005","article-title":"Global prevalent use, trends and practices in haemodiafiltration","volume":"35","author":"B Canaud","year":"2020","journal-title":"Nephrol Dial Transplant"},{"issue":"12","key":"pone.0314030.ref013","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1002\/cpdd.1160","article-title":"Population Pharmacokinetics of Oral Migalastat in Adolescents and Adults With and Without Renal Impairment","volume":"11","author":"C Leonowens","year":"2022","journal-title":"Clin Pharmacol Drug Dev"},{"issue":"9","key":"pone.0314030.ref014","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1002\/cpdd.941","article-title":"Migalastat Tissue Distribution: Extrapolation From Mice to Humans Using Pharmacokinetic Modeling and Comparison With Agalsidase Beta Tissue Distribution in Mice","volume":"10","author":"YS Wu","year":"2021","journal-title":"Clin Pharmacol Drug Dev"},{"key":"pone.0314030.ref015","unstructured":"Amicus Therapeutics, Inc. 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