Preclinical Evaluation of the Oral Toxicity, Genotoxicity, and Safety Pharmacology of LPM4870108, a Novel Potent Tropomyosin Receptor Kinase Inhibitor.

Abstract

Tropomyosin receptor kinase (Trk) inhibitors are an essential class of anticancer drugs treating NTRK gene fusions-positive cancer. However, the potential for the emergence of on-target resistance suggests newer Trk inhibitors with low drug resistance risk are needed. LPM4870108 is a novel Trk inhibitor with robust anticancer efficacy in preclinical studies. To support future clinical development, this study systematically evaluated the acute and subacute (4-week) toxicity, toxicokinetic, genotoxic, and safety pharmacology of LPM4870108. The acute toxicity study revealed the maximum tolerated dose of LPM4870108 was 300 mg/kg, whereas subacute studies determined its STD₁₀ in rats was 10 mg/kg/day. The toxicological effects of LPM4870108 were consistent with its pharmacodynamic efficacies as a Trk inhibitor, including corneal inflammation, splenic lymphocytopenia, hepatocyte vacuolar degeneration, scab formation, and increased food consumption and body weight. These changes were partially or fully recovered after 4 weeks of recovery. In rats treated with 10 or 20 mg/kg/day, 2/30, or 6/30 rats died or were moribund, and the primary organs affected by treatment-related toxicity included the eyes, liver, and skin. Rat toxicokinetic findings were consistent with a dose-dependent effect of LPM4870108. There was no evidence of LPM4870108-related genotoxicity, nor did it affect respiratory function or neurobehavioral activity in rats or blood pressure or electrocardiogram results in rhesus monkeys. The IC₅₀ of LPM4870108 for hERG current inhibition was 18.2 μM. Together, these results demonstrate that LPM4870108 exhibits a satisfactory safety profile which is appropriate for further clinical development.