Pharmacokinetics of Polyethylene Glycol-Modified Canine Uricase Following Single and Multiple Intravenous Injections in Cynomolgus Monkeys

Autor: Li, Haigang, Huo, JingJing, Sun, Dan, Jiang, Liang, Hu, Chunlan, Bai, Yanmin, Ma, Xuefeng, Zhang, Haijuan, Shi, Xiaowei, Zhao, Zhilong, Zhou, Jinchuan, Lu, Yongxin, Zhang, Chun
Zdroj: European Journal of Drug Metabolism and Pharmacokinetics; 20240101, Issue: Preprints p1-7, 7p
Abstrakt: Background and Objective: Polyethylene glycol-modified canine uricase (PEG-UHC) prepared with a lower-molecular-weight (5 kDa) PEG is used to treat gout. This study investigated the comparative pharmacokinetics of single and multiple doses of PEG-UHC administered intravenously and a single dose of uricase (UHC) administered intravenously in cynomolgus monkeys. Methods: A noncompartmental model was used to fit the plasma drug concentration–time curve and calculate the pharmacokinetic parameters of PEG-UHC, which were compared with those obtained for UHC at the equivalent dose (2 mg/kg). To study the pharmacokinetics after multiple dose administration, cynomolgus monkeys were administered five intravenous injections of PEG-UHC (0.5 mg/kg), with one injection performed every 15 days. Results: The area under the curve (AUC) and the maximum plasma concentration (Cmax) of PEG-UHC were positively correlated with dose, whereas plasma half-life (t1/2) and clearance (CL) did not change significantly with increasing dose, suggesting that these pharmacokinetic characteristics are linear. Intravenous PEG-UHC exhibited an average t1/2that was 125.79 times longer and an AUC0−tthat was 64.45 times larger than the corresponding values for UHC at the same dose (2 mg/kg), while the CL of PEG-UHC was 1/72.73 times the CL of intravenous UHC. The plasma drug concentration reached a steady state after five injections, and the t1/2values following the first and last drug administration did not differ significantly. Conclusion: Our data show that PEG-UHC is markedly superior to UHC in terms of duration of action, and that the pharmacokinetics of PEG-UHC in cynomolgus monkeys are linear. Sequential administration of PEG-UHC did not accelerate drug clearance. Our findings provide the basis for future clinical studies of PEG-UHC.
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