{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T08:47:19Z","timestamp":1788425239580,"version":"build-2803163510"},"reference-count":28,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T00:00:00Z","timestamp":1622419200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008484","name":"BioMarin Pharmaceutical","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008484","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Phenylketonuria (PKU), a deficiency in the activity of the enzyme phenylalanine hydroxylase, leads to toxic levels of phenylalanine (Phe) in the blood and brain. Pegvaliase (recombinant <jats:italic>Anabaena<\/jats:italic> <jats:italic>variabilis<\/jats:italic> phenylalanine ammonia lyase conjugated with polyethylene glycol) is approved to manage PKU in patients aged greater than or equal to 18\u00a0years in the United States and in patients aged greater than or equal to 16\u00a0years in the European Union. Pharmacokinetic, pharmacodynamic, and immunogenicity results from five open\u2010label pegvaliase trials were assessed. Studies with induction\/titration\/maintenance (I\/T\/M) dosing regimens demonstrated pharmacokinetic stabilization and sustained efficacy associated with maintenance doses (20, 40, or 60\u00a0mg\/day). Immune\u2010mediated pegvaliase clearance was high during induction\/titration phases when the early immune response was peaking. The combination of low drug dosage and high drug clearance led to low drug exposure and minimal decreases in blood Phe levels during induction\/titration. Higher drug exposure and substantial reductions in blood Phe levels were observed later in treatment as drug clearance was reduced due to the maturation of the immune response, which allowed for increased dosing to target levels. The incidence of hypersensitivity reactions was temporally associated with the peaking of the early antidrug immune response and decreased with time as immune response matured after the first 6\u00a0months of treatment. These results support an I\/T\/M dosing regimen and suggest a strategy for administration of other nonhuman biologics to achieve efficacy and improve tolerability.<\/jats:p>","DOI":"10.1111\/cts.13043","type":"journal-article","created":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T12:34:26Z","timestamp":1622464466000},"page":"1894-1905","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Pharmacokinetic, pharmacodynamic, and immunogenic rationale for optimal dosing of pegvaliase, a PEGylated bacterial enzyme, in adult patients with phenylketonuria"],"prefix":"10.1111","volume":"14","author":[{"given":"Yulan","family":"Qi","sequence":"first","affiliation":[{"name":"BioMarin Pharmaceutical Inc Novato CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gina","family":"Patel","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical Inc Novato CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Henshaw","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical Inc Novato CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumi","family":"Gupta","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical Inc Novato CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joy","family":"Olbertz","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical Inc Novato CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Larimore","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical Inc Novato CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cary O.","family":"Harding","sequence":"additional","affiliation":[{"name":"Department of Molecular and Medical Genetics Oregon Health &amp; Science University Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Merilainen","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical Inc Novato CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Zori","sequence":"additional","affiliation":[{"name":"Division of Genetics and Metabolism University of Florida Gainesville FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Longo","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics University of Utah Salt Lake City UT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara K.","family":"Burton","sequence":"additional","affiliation":[{"name":"Division of Genetics, Birth Defects and Metabolism Ann &amp; Robert H. 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