Toxicological and Metabolic Considerations for histone deacetylase inhibitors

Introduction: Vorinostat and romidepsin were the first histone deacetylase (HDAC)
inhibitors (HDi) that fulfilled the preclinical promise of anticancer potential in clinical
trials. Nevertheless, they merely opened a new chapter in the history of cancer
therapy. Demonstration of their antitumour activity was a straightforward task in in
vitro setting. Proving their efficacy in vivo was much more difficult, since the effects
of an administrated drug strongly depend on its absorption, distribution, metabolism
and excretion.
Areas covered: This article summarizes clinical data on the pharmacokinetics
properties of HDi that are currently at more advanced stages of clinical
development. Specific attention is paid to the metabolic pathways. Moreover, a
comprehensive overview of HDi-related adverse effects is given.
Expert opinion: At this moment, HDi form one of the most interesting classes of
therapeutics, yet their efficacy and safety profiles could still be improved by (i)
designing better formulations, (ii) more extensive characterization of their
disposition at the preclinical stage, (iii) targeting of individual disease-related
deacetylase isoforms and/or their complexes, (iv) selecting a target patient
population with the highest probability of response based on molecular signatures.