Optimization of HDAC Inhibitor Dosing

For vorinostat (Sigma), we chose a range of 50nM– 1 μM. The high dose of 1μM was chosen as it was used in in vitro latency experiments and the peak serum concentration of vorinostat in vivo was reported to be 1.2μM; however as the free concentration of vorinostat was only 360nM [27 (link)], we used 333nM as our physiologically relevant dose. For panobinostat (Cambridge Bioscience), we chose a range from 5-100nM. The mean clinical C_max of panobinostat at the 20mg p.o. dosing of the CLEAR trial is 40nM [28 (link)]and the steady-state plasma concentration is 15-22nM [7 (link)] so we chose 20nM as our physiological dose. For romidepsin (Abcam), we chose a range of 5-100nM to match our panobinostat range. The peak serum concentration for clinical doses is 698nM with free drug concentration being 56nM [27 (link)]. We thus chose 10nM, which incorporated our cell line toxicity studies. We used 300nM prostratin based on other ex vivo studies [29 (link)].