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Belinostat is predominantly metabolized by UGT1A1, which is polymorphic. Preliminary analyses revealed a difference in belinostat clearance based on <jats:italic>UGT1A1<\/jats:italic> genotype. A 2\u2010compartment population pharmacokinetic (PK) model was developed and validated that incorporated the <jats:italic>UGT1A1<\/jats:italic> genotype, albumin, and creatinine clearance on the clearance parameter; body weight was a significant covariate on volume. Simulated doses of 600 and 400\u2009mg\/m<jats:sup>2<\/jats:sup>\/24\u2009h given to patients considered extensive or impaired metabolizers, respectively, provided equivalent AUCs. This model and subsequent simulations supported additional PK\/toxicity and pharmacogenomics\/toxicity analyses to suggest a <jats:italic>UGT1A1<\/jats:italic> genotype\u2010based dose adjustment to normalize belinostat exposure and allow for more tolerable therapy. In addition, global protein lysine acetylation was modeled with PK and demonstrated a reversible belinostat exposure\/response relationship, consistent with previous reports.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcph.627","type":"journal-article","created":{"date-parts":[[2015,12,4]],"date-time":"2015-12-04T15:02:07Z","timestamp":1449241327000},"page":"450-460","source":"Crossref","is-referenced-by-count":18,"title":["<i>UGT1A1<\/i> genotype\u2010dependent dose adjustment of belinostat in patients with advanced cancers using population pharmacokinetic modeling and simulation"],"prefix":"10.1002","volume":"56","author":[{"given":"Cody J.","family":"Peer","sequence":"first","affiliation":[{"name":"Clinical Pharmacology Program National Cancer Institute NIH, Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew K. 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