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: 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
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 56 Issue 4 Pg. 450-60 (Apr 2016) ISSN: 1552-4604 [Electronic] England
• PMID: 26637161 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Intramural)
• Copyright: © 2015, The American College of Clinical Pharmacology.

Chemical References

• Albumins
• Antineoplastic Agents
• Hydroxamic Acids
• Sulfonamides
• Creatinine
• UGT1A1 enzyme
• Glucuronosyltransferase
• belinostat

Topics

• Adult
• Aged
• Albumins (metabolism)
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Creatinine (metabolism)
• Female
• Genotype
• Glucuronosyltransferase (genetics)
• Humans
• Hydroxamic Acids (administration & dosage, pharmacokinetics)
• Kinetics
• Male
• Middle Aged
• Models, Biological
• Neoplasms (drug therapy, genetics, metabolism)
• Pharmacogenetics (methods)
• Sulfonamides (administration & dosage, pharmacokinetics)