LPM4870108 is a
tropomyosin receptor
kinase (Trk) inhibitor that is currently under consideration for human clinical trials. We characterized the toxicity and toxicokinetic properties of
LPM4870108 following its
oral administration to rhesus monkeys (5, 10, or 20 mg/kg/day for 4 weeks with a 4-week recovery period). No evidence of
LPM4870108 toxicity was observed over this study as reflected by an absence of difference in
body weight, ophthalmoscopy, urinalysis, gross, or histopathology findings. No significant differences in toxicity-related outcomes were detected when comparing
LPM4870108 and control groups, and no significant treatment-related changes in food consumption, electrocardiogram results, blood pressure, hematological parameters, biochemical values, organ weight, or bone marrow parameters were observed. Treatment caused dose-dependent effects of gait disturbance, impaired balance, poor coordination, and decreased grip strength in all LPM4870108-treated animals, with these effects being attributable to excessive on-target Trk receptor inhibition. After the 4-week recovery period, all these abnormal treatment-related findings had fully or partially resolved. The toxicokinetic study of monkeys revealed that the
LPM4870108 exposure increased with dose. Overall,
LPM4870108 exhibited a safety profile in treated monkeys, indicating that the Highest Non-Severely Toxic Dose (HNSTD) for
LPM4870108 in monkeys was 20 mg/kg/day.