title: UGT1A1 genotype-dependent dose adjustment of belinostat in patients with advanced cancers using population pharmacokinetic modeling and simulation.
abstract: Belinostat is a second-generation zinc-binding histone deacetylase inhibitor that is approved for peripheral T-cell lymphoma and is currently being studied in small cell lung cancer and other advanced carcinomas as a 48-hour continuous intravenous infusion. Belinostat is predominantly metabolized by UGT1A1, which is polymorphic. Preliminary analyses revealed a difference in belinostat clearance based on UGT1A1 genotype. A 2-compartment population pharmacokinetic (PK) model was developed and validated that incorporated the UGT1A1 genotype, albumin, and creatinine clearance on the clearance parameter; body weight was a significant covariate on volume. Simulated doses of 600 and 400 mg/m(2) /24 h 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 UGT1A1 genotype-based 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.
authors.affiliation: Clinical Pharmacology Program, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Cody J
authors.initials: CJ
authors.lastname: Peer
authors.affiliation: Clinical Pharmacology Program, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Andrew K L
authors.initials: AK
authors.lastname: Goey
authors.affiliation: Clinical Pharmacology Program, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Tristan M
authors.initials: TM
authors.lastname: Sissung
authors.affiliation: Clinical Pharmacology Program, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Sheryl
authors.initials: S
authors.lastname: Erlich
authors.affiliation: Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tomita
authors.affiliation: Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Piekarz
authors.affiliation: Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Sanjeeve
authors.initials: S
authors.lastname: Balasubramaniam
authors.affiliation: Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
authors.affiliation: Clinical Pharmacology Program, National Cancer Institute, NIH, Bethesda, MD, USA.|Genitourinary Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
mesh_terms: D000328:Adult; D000368:Aged; D000418:Albumins / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D003404:Creatinine / Q000378:metabolism; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics / Q000379:methods; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000099148:UGT1A1 Enzyme
chemical_list: D000418:Albumins; D000970:Antineoplastic Agents; D003404:Creatinine; D014453:Glucuronosyltransferase; D006877:Hydroxamic Acids; D013449:Sulfonamides; D000099148:UGT1A1 Enzyme; C487081:belinostat
keywords: clinical pharmacology; oncology; pharmacogenetics; pharmacokinetics; pharmacometrics; population