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Toxicokinetics of recombinant human fibroblast growth factor 21 for injection in cynomolgus monkey for 3 months
Chao Lu1,2,3, Lei Jin2,3, Jianing Bi1
1Department of Neurological Rehabilitation, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Abstract:
Introduction: Recombinant human fibroblast growth factor 21 (FGF-21) is a potential therapeutic agent for multiple metabolic diseases. However, little is known about the toxicokinetic characteristics of FGF-21. Methods: In the present study, we investigated the toxicokinetics of FGF-21 delivered via subcutaneous injection in vivo. Twenty cynomolgus monkeys were injected subcutaneously with different doses of FGF-21 for 86 days. Serum samples were collected at eight different time points (0, 0.5, 1.5, 3, 5, 8, 12, and 24 h) on day 1, 37 and 86 for toxicokinetic analysis. The serum concentrations of FGF-21 were measured using a double sandwich Enzyme-linked immunosorbent assay. Blood samples were collected on day 0, 30, 65, and 87 for blood and blood biochemical tests. Necropsy and pathological analysis were performed on d87 and d116 (after recovery for 29 days). Results: The average AUC(0-24h) values of low-dose FGF-21 on d1, d37, and d86 were 5253, 25268, and 60445 μg h/L, and the average AUC(0-24h) values of high-dose FGF-21 on d1, d37, and d86 were 19964, 78999, and 1952821 μg h/L, respectively. Analysis of the blood and blood biochemical indexes showed that prothrombin time and AST content in the high-dose FGF-21 group increased. However, no significant changes in other blood and blood biochemical indexes were observed. The anatomical and pathological results showed that continuous subcutaneous injection of FGF-21 for 86 days did not affect organ weight, the organ coefficient, and histopathology in cynomolgus monkeys. Discussion: Our results have guiding significance for the preclinical research and clinical use of FGF-21.
Insights
Recombinant human fibroblast growth factor 21 (FGF-21) toxicokinetics were studied in monkeys. High-dose FGF-21 increased prothrombin time and AST, but no significant organ pathology was observed, guiding its clinical use.
Area of Science:
- Pharmacology
- Toxicology
- Metabolic Diseases
Background:
- Recombinant human fibroblast growth factor 21 (FGF-21) shows therapeutic potential for metabolic diseases.
- Limited data exists on the toxicokinetic profile of FGF-21.
Purpose of the Study:
- To investigate the toxicokinetic characteristics of FGF-21 following subcutaneous administration in cynomolgus monkeys.
- To assess the safety and potential toxic effects of FGF-21 over an 86-day period.
Main Methods:
- Subcutaneous injection of varying FGF-21 doses in 20 cynomolgus monkeys for 86 days.
- Toxicokinetic analysis of serum FGF-21 concentrations via ELISA at multiple time points.
- Evaluation of blood biochemical parameters, organ weights, and histopathology post-treatment and recovery.
Main Results:
- Area Under the Curve (AUC) for FGF-21 increased with dose and duration, particularly in the high-dose group.
- Elevated prothrombin time and AST levels were observed in the high-dose FGF-21 group.
- No significant adverse effects on organ weight, organ coefficient, or histopathology were detected.
Conclusions:
- Subcutaneous FGF-21 administration demonstrates dose- and time-dependent toxicokinetics in cynomolgus monkeys.
- While some biochemical changes occurred at high doses, FGF-21 did not induce significant organ toxicity.
- These findings provide crucial insights for the preclinical and clinical development of FGF-21 therapies.
