Pathology and Neurotoxicity in Dogs after Repeat Dose Exposure to a Serotonin 5-HT1B Inhibitor

AZD3783, a cationic amphiphilic drug and a potent inhibitor of the 5-hydroxytryptamine(5-HT_1B) receptor, was explored as a potential treatment for depression. Tosupport clinical trials, repeat dose toxicity studies in rats and dogs were conducted.Here we report toxicity findings in dogs after dosing from 1 to 3 months. In the 1-monthstudy, there were minimal neuronal vacuolation in the brain, a marked increase in liverenzymes accompanied by hepatocellular degeneration/necrosis and phospholipidosis (PLD),and PLD/cholecystitis in the gallbladder of animals dosed at 47 mg/kg/day. In the 3-monthstudy, neurotoxicity resulted in euthanasia of one animal dosed at 30 mg/kg/day after 86days. Extensive pathologic changes were seen in all animals in retina epithelium(inclusion bodies), brain (neuronal vacuolation, degeneration, or necrosis and nerve fiberdegeneration), spinal ganglia (vacuolation, degeneration, or necrosis), as well as sciaticand optic nerves (degeneration). Pigment-laden macrophages were observed in the lung,kidney, liver, gallbladder, bone marrow, gastrointestinal tract, and lymphoid tissues.Also seen were vitrel and retinal hemorrhage in the eyes. A brain concentration andpathology study showed that the concentration of AZD3783 in the brain was approximately 4times higher than in the plasma after 4 weeks of dosing, however, they were similar in allregions examined, and did not correlate with areas with pathologic findings. Our findingswith AZD3783 in dogs have not been reported previously with other CNS compounds thateffect through serotonergic pharmacology.