Lymphoid depletion with atrophy of thymus, lymph nodes, bone marrow and spleen; partially reversible
“This lymphoid depletion led to atrophies of thymus, lymph nodes, bone marrow and spleen. This interference of givinostat with the white blood cell lineage likely reflects its anti-inflammatory activity and was partially reversible in rats and monkeys.”
Rat: mainly GI tract and elimination organs (liver, kidney, bladder); no significant brain distribution
“In rats, givinostat primarily distributed into gastrointestinal tract tissue (intestine > duodenum > stomach) and in organs involved in elimination (liver > kidney > bladder), but not significantly into the brain.”
No exposure-based safety margins at repeat-dose NOAELs relative to therapeutic doses
“However, no relevant Cmax- and AUC-based safety margins could be established for givinostat at the respective NOAELs in subchronic and chronic toxicity studies in mice, rats and monkeys compared to the envisaged therapeutic human doses of 25 to 70 mg bid in DMD patients.”