Pharmacokinetic and Pharmacodynamic Evaluation ombined Valproic Acid/Doxorubicin Treatment in Dogs

Download pose: Histone deacetylase inhibitors (HDACi) are targeted anticancer agents with a well-documenility to act synergistically with cytotoxic agents. We recently showed that the HDACi valproic acid izes osteosarcoma cells to doxorubicin in vitro and in vivo. As there are no published reports on the l utility of HDACi in dogs with spontaneous cancers, we sought to determine a safe and biologiffective dose of valproic acid administered prior to a standard dose of doxorubicin. hods: Twenty-one dogs were enrolled into eight cohorts in an accelerated dose-escalation trial conof pretreatment with oral valproic acid followed by doxorubicin on a three-week cycle. Blood and tissue were collected for determination of serum valproic acid concentration and evaluation of acodynamic effects by immunofluorescence cytochemistry and immunohistochemistry. Serum mplete blood counts were obtained for determination of changes in doxorubicin pharmacokinetics atologic effects. ults: All doses of valproic acid were well tolerated. Serum valproic acid concentrations increased ly with dose. Doxorubicin pharmacokinetics were comparable with those in dogs receiving doxon alone. A positive correlation was detected between valproic acid dose and histone hyperacetylaperipheral blood mononuclear cells. No potentiation of doxorubicin-induced myelosuppression bserved. Histone hyperacetylation was documented in tumor and peripheral blood mononuclear Responses included 2 of 21 complete, 3 of 21 partial, 5 of 21 stable disease, and 11 of 21 proe disease. clusions: Valproic acid can be administered to dogs at doses up to 240 mg/kg/day prior to a stanose of doxorubicin. In addition, we have developed the pharmacokinetic/pharmacodynamic tools dard d necessary for future studies of novel HDACi in the clinical setting of canine cancer. Clin Cancer Res; 16(19);