{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:03:11Z","timestamp":1773878591068,"version":"3.50.1"},"reference-count":39,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2014,12,9]],"date-time":"2014-12-09T00:00:00Z","timestamp":1418083200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"funder":[{"DOI":"10.13039\/100008484","name":"BioMarin Pharmaceutical, Inc","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008484","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2015,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The clinical use of amifampridine phosphate for neuromuscular junction disorders is increasing. The metabolism of amifampridine occurs via polymorphic aryl<jats:italic>N<\/jats:italic>\u2010acetyltransferase (<jats:styled-content style=\"fixed-case\">NAT<\/jats:styled-content>), yet its pharmacokinetic (<jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>) and safety profiles, as influenced by this enzyme system, have not been investigated. The objective of this study was to assess the effect of<jats:styled-content style=\"fixed-case\">NAT<\/jats:styled-content>phenotype and genotype on the<jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>and safety profiles of amifampridine in healthy volunteers (<jats:italic>N\u00a0<\/jats:italic>=<jats:italic>\u00a0<\/jats:italic>26). A caffeine challenge test and<jats:styled-content style=\"fixed-case\">NAT<\/jats:styled-content>2 genotyping were used to delineate subjects into slow and fast acetylators for<jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>and tolerability assessment of single, escalating doses of amifampridine (up to 30\u00a0mg) and in multiple daily doses (20\u00a0mg<jats:styled-content style=\"fixed-case\">QID<\/jats:styled-content>) of amifampridine. The results showed that fast acetylator phenotypes displayed significantly lower<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>,<jats:styled-content style=\"fixed-case\">AUC<\/jats:styled-content>, and shorter<jats:italic>t<\/jats:italic><jats:sub>1\/2<\/jats:sub>for amifampridine than slow acetylators. Plasma concentrations of the<jats:italic>N<\/jats:italic>\u2010acetyl metabolite were approximately twofold higher in fast acetylators. Gender differences were not observed. Single doses of amifampridine demonstrated dose linear<jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>s. Amifampridine achieved steady state plasma levels within 1\u00a0day of dosing four times daily. No accumulation or time\u2010dependent changes in amifampridine<jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>parameters occurred. Overall, slow acetylators reported 73 drug\u2010related treatment\u2010emergent adverse events versus 6 in fast acetylators. Variations in polymorphic<jats:styled-content style=\"fixed-case\">NAT<\/jats:styled-content>corresponding with fast and slow acetylator phenotypes significantly affects the<jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>and safety profiles of amifampridine.<\/jats:p>","DOI":"10.1002\/prp2.99","type":"journal-article","created":{"date-parts":[[2014,12,9]],"date-time":"2014-12-09T08:58:42Z","timestamp":1418115522000},"source":"Crossref","is-referenced-by-count":19,"title":["Genetic variation in aryl<i>N<\/i>\u2010acetyltransferase results in significant differences in the pharmacokinetic and safety profiles of amifampridine (3,4\u2010diaminopyridine) phosphate"],"prefix":"10.1002","volume":"3","author":[{"given":"Peter E.","family":"Haroldsen","sequence":"first","affiliation":[{"name":"BioMarin Pharmaceutical Inc. Novato California 94949"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marvin R.","family":"Garovoy","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical Inc. Novato California 94949"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donald G.","family":"Musson","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical Inc. Novato California 94949"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huiyu","family":"Zhou","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical Inc. Novato California 94949"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurie","family":"Tsuruda","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical Inc. Novato California 94949"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boyd","family":"Hanson","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical Inc. Novato California 94949"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles A.","family":"O'Neill","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical Inc. Novato California 94949"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,12,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1990.sp018333"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.patbio.2011.07.001"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410270411"},{"key":"e_1_2_10_5_1","first-page":"581","article-title":"Arylamine N\u2010acetyltransferase (NAT2) mutations and their allelic linkage in unrelated Caucasian individuals: correlation with phenotypic activity","volume":"57","author":"Cascorbi I","year":"1995","journal-title":"Am J Hum Genet"},{"key":"e_1_2_10_6_1","unstructured":"Firdapse\u00ae Tablets Prescribing Information(2013).EMA product number EMEA\/H\/C\/001032.BioMarin Europe Ltd London UK. 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