2. Academic Validation
  3. Assessment of the toxicity and toxicokinetics of the novel potent tropomyosin receptor kinase (Trk) inhibitor LPM4870108 in rhesus monkeys

Assessment of the toxicity and toxicokinetics of the novel potent tropomyosin receptor kinase (Trk) inhibitor LPM4870108 in rhesus monkeys

  • Regul Toxicol Pharmacol. 2021 Jun;122:104886. doi: 10.1016/j.yrtph.2021.104886.
Sijin Duan 1,  Lin Dong 2,  Bingsi Wang 2,  Shujuan Wei 2,  Xiaoyan Gong 2,  Pengfei Yu 3,  Chunmei Li 1,  Yonglin Gao 4,  Liang Ye 3,  Hongbo Wang 5,  Jingwei Tian 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, PR China.
  • 2 State Key Laboratory of Long-acting Targeting Drug Delivery Technologies (Luye Pharma Group Ltd.), Yantai, 264003, PR China.
  • 3 School of Public Health and Management, Binzhou Medical University, Yantai, 264003, PR China.
  • 4 School of Life Science, Yantai University, Yantai, 264005, PR China.
  • 5 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, PR China. Electronic address: hongbowang@ytu.edu.cn.
  • 6 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, PR China. Electronic address: Tianjingwei618@163.com.
PMID: 33556418 DOI: 10.1016/j.yrtph.2021.104886
Abstract

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.

Keywords

LPM4870108; Oral toxicity study; Preclinical safety assessment; Rhesus monkeys; Toxicokinetics; Tropomyosin receptor kinase (Trk) inhibitor.

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