title: Effects of UGT1A1 genotype on the pharmacokinetics, pharmacodynamics, and toxicities of belinostat administered by 48-hour continuous infusion in patients with cancer.
abstract: The histone deacetylase inhibitor belinostat is eliminated through glucuronidation by UGT1A1. Polymorphisms that reduce UGT1A1 function could result in increased belinostat exposure and toxicities. We wanted to determine which single-nucleotide polymorphisms alter belinostat exposure and toxicity. In a phase 1 trial (belinostat over 48 hours in combination with cisplatin and etoposide), belinostat (400, 500, 600, or 800 mg/m(2) /24 h, 48-hour continuous infusion) was administered to patients with cancer in combination with cisplatin and etoposide (n = 25). Patients were genotyped for UGT1A1 variants associated with reduced function: UGT1A1*6, UGT1A1*28, and UGT1A1*60. End points were associations between UGT1A1 genotype and belinostat pharmacokinetics (PK), toxicities, and global protein lysine acetylation (AcK). Belinostat AUC was increased (P = .003), and t1/2 increased (P = .0009) in UGT1A1*28 and UGT1A1*60 carriers who received more than 400 mg/m(2) /24 h. The incidence of grades 3-4 thrombocytopenia (P = .0081) was associated with UGT1A1 polymorphisms. The US Food and Drug Administration-approved package insert recommends dose adjustment of belinostat for UGT1A1*28. However, our data suggest dose adjustment is also necessary for UGT1A1*60. UGT1A1 polymorphisms were associated with increased systemic belinostat exposure, increased AcK, and increased incidence of toxicities, particularly at doses > 400 mg/m(2) /24 h.
authors: Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Andrew K L
authors: AK
authors: Goey
authors: Molecular Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Tristan M
authors: TM
authors: Sissung
authors: Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Cody J
authors: CJ
authors: Peer
authors: Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Jane B
authors: JB
authors: Trepel
authors: Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Min-Jung
authors: MJ
authors: Lee
authors: Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Yusuke
authors: Y
authors: Tomita
authors: Molecular Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Sheryl
authors: S
authors: Ehrlich
authors: Medical Oncology Service, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Christine
authors: C
authors: Bryla
authors: Medical Oncology Service, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Sanjeeve
authors: S
authors: Balasubramaniam
authors: Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Richard
authors: R
authors: Piekarz
authors: Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Seth M
authors: SM
authors: Steinberg
authors: Medical Oncology Service, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Susan E
authors: SE
authors: Bates
authors: Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: William D
authors: WD
authors: Figg
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002945:Cisplatin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000099148:UGT1A1 Enzyme
chemical_list: D002945:Cisplatin; D005047:Etoposide; D014453:Glucuronosyltransferase; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; D000099148:UGT1A1 Enzyme; C487081:belinostat
keywords: UGT1A1; belinostat; pharmacodynamics; pharmacogenomics; pharmacokinetics