UGT1A1 genotype-dependent dose adjustment of belinostat in patients with advanced cancers using population pharmacokinetic modeling and simulation

Cody J. Peer, Andrew K.L. Goey, Tristan M. Sissung, Sheryl Erlich, Min Jung Lee, Yusuke Tomita, Jane B. Trepel, Richard Piekarz, Sanjeeve Balasubramaniam, Susan E. Bates, William D. Figg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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/m2/24 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.

Original languageEnglish
Pages (from-to)450-460
Number of pages11
JournalJournal of Clinical Pharmacology
Volume56
Issue number4
DOIs
StatePublished - 1 Apr 2016
Externally publishedYes

Keywords

  • clinical pharmacology
  • oncology
  • pharmacogenetics
  • pharmacokinetics
  • pharmacometrics
  • population

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