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UGT1A1 genotype-dependent dose adjustment of belinostat in patients with advanced cancers using population

Cody J Peer1, Andrew K L Goey1, Tristan M Sissung1

  • 1Clinical Pharmacology Program, National Cancer Institute, NIH, Bethesda, MD, USA.

Journal of Clinical Pharmacology
|December 5, 2015
PubMed

Insights

Belinostat

Area of Science:

  • Pharmacology
  • Oncology
  • Genetics

Background:

  • Belinostat is a histone deacetylase inhibitor used for peripheral T-cell lymphoma.
  • Its metabolism is primarily influenced by the polymorphic UGT1A1 enzyme.
  • Patient UGT1A1 genotype may affect belinostat clearance.

Purpose of the Study:

  • To develop and validate a pharmacokinetic model for belinostat.
  • To investigate the impact of UGT1A1 genotype on belinostat exposure.
  • To explore genotype-based dose adjustments for improved tolerability.

Main Methods:

  • A 2-compartment population pharmacokinetic model was developed.
  • Covariates included UGT1A1 genotype, albumin, and creatinine clearance.
  • Simulations were used to assess dose adjustments for different metabolizer phenotypes.

Main Results:

  • UGT1A1 genotype, albumin, and creatinine clearance significantly impacted belinostat clearance.
  • Body weight was a covariate on volume.
  • Simulated doses normalized area under the curve (AUC) between extensive and impaired metabolizers.

Conclusions:

  • A UGT1A1 genotype-based dose adjustment can normalize belinostat exposure.
  • This approach may lead to more tolerable belinostat therapy.
  • A reversible belinostat exposure/response relationship was observed.
Keywords:
clinical pharmacologyoncologypharmacogeneticspharmacokineticspharmacometricspopulation

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