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

Abstract：

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 t1/2 that was 125.79 times longer and an AUC0-t that 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 t1/2 values 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.

journal_name

Eur J Drug Metab Pharmacokinet

journal_title

European journal of drug metabolism and pharmacokinetics

authors

Li H,Huo J,Sun D,Jiang L,Hu C,Bai Y,Ma X,Zhang H,Shi X,Zhao Z,Zhou J,Lu Y,Zhang C

doi

10.1007/s13318-020-00612-w

subject

Has Abstract

pub_date

2020-08-01 00:00:00

pages

445-451

issue

eissn

0378-7966

issn

2107-0180

pii

10.1007/s13318-020-00612-w

journal_volume

pub_type

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