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A population pharmacokinetic/toxicity model for the reduction of platelets during a 48-h continuous intravenous infusion of the histone deacetylase inhibitor belinostat

Authors :
William D. Figg
Sanjeeve Balasubramaniam
Susan E. Bates
Richard Piekarz
Oliver Morgan Hall
Cody J. Peer
Tristan M. Sissung
Source :
Cancer Chemotherapy and Pharmacology. 82:565-570
Publication Year :
2018
Publisher :
Springer Science and Business Media LLC, 2018.

Abstract

PURPOSE: Belinostat is a second-generation histone deacetylase inhibitor (HDI) predominantly metabolized by UGT1A1-mediated glucuronidation. Two common polymorphisms (UGT1A1*28 and UGT1A1*60) were previously associated with impaired drug clearance and thrombocytopenia risk, likely form increased drug exposure. This latter phenomenon has been observed with other HDIs such as abexinostat, panobinostat, romidepsin, and vorinostat. It was the intention of this brief report to expand a population pharmacokinetic (PPK) model to include a pharmacodynamic (PD) model describing the change in platelet levels in patients with cancer administered belinostat as a 48-h continuous intravenous infusion, along with cisplatin and etoposide. METHODS: The PPK/PD model developed here introduced an additional rate constant to a commonly used mechanistic myelo-suppression model to better describe the maturation of megakaryocytes into platelets before degradation and a feedback mechanism. The model employed a proportional error model to describe the observed circulating platelet data. RESULTS: Several covariates were explored, including sex, body weight, UGT1A1 genotype status, liver, and kidney function, but none significantly improved the model. Platelet levels rebounded to baseline within 21 days, before the next cycle of therapy. Simulations predicted that higher belinostat drug exposure does cause lower thrombocyte nadirs compared to lower belinostat levels. However, platelet levels rebound by the start of the next belinostat cycle. CONCLUSIONS: This model suggests a q3week schedule allows for sufficient platelet recovery before the next belinostat infusion is optimal.

Details

ISSN :
14320843 and 03445704
Volume :
82
Database :
OpenAIRE
Journal :
Cancer Chemotherapy and Pharmacology
Accession number :
edsair.doi.dedup.....85b634a6c8889b2e6f5585382d287579