Abstract
Aim:
Pharmacodynamic analysis of intravenous recombinant urate oxidase produced by Escherichia coli was performed in healthy subjects using a pharmacokinetic/pharmacodynamic (PK/PD) model.
Methods:
A randomized, single-blind, placebo-controlled study was performed in 40 healthy Chinese subjects (4 groups of 10 subjects each, placebo 4:1 ratio) who received infusions of uricase (single doses of 0.1, 0.2, and 0.3 mg/kg; multiple doses of 0.2 mg·kg−1·d−1 for 7 d). PK profiles were determined through plasma uricase activity, and PD profiles were established using uric acid levels in plasma and urine. The plasma PD parameter was estimated as changes in plasma uric acid levels as the effect in the indirect response model. Adverse events were also monitored.
Results:
A two-compartment PK model with constant iv input and first-order output was used to describe the kinetic process of plasma uricase. The low value (2.8 U/L) of drug concentration that achieved 50% of maximum effect (EC50) indicated that low plasma uricase concentrations were sufficient to produce pharmacological effects. A strong relationship (r2=0.9991) between the mean uric acid concentration in blood and the mean uric acid excretion rate in urine in the range of 11 to 30 h after single dosing was found. Infusions of uricase were well tolerated in all subjects.
Conclusion:
The PK/PD model predicted the effective dose to be 0.1 mg/kg in healthy subjects. The excretion rate of uric acid in urine may be used as a new index for pharmacological effects in further clinical trials.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Pui CH . Rasburicase: a potent uricolytic agent. Expert Opin Pharmacother 2002; 3: 433–42.
Greene ML, Fujimoto WY, Seegmiller JE . Urinary xanthine stones — a rare complication of allopurinol therapy. N Engl J Med 1969; 280: 426–7.
Andreoli SP, Clark JH, McGuire WA, Bergstein JM . Purine excretion during tumor lysis in children with acute lymphocytic leukemia receiving allopurinol: relationship to acute renal failure. J Pediatric 1986; 109: 292–8.
Liu CY, Sims-McCallum RP, Schiffer CA . A single dose of rasburicase is sufficient for the treatment of hyperuricemia in patients receiving chemotherapy. Leukemia Res 2005; 29: 463–5.
Leplatois P, Le Douarin B, Loison G . High-level production of a peroxisomal enzyme: aspergillus flavus uricase accumulates intracellularly and is active in Saccharomyces cerevisiae. Gene 1992; 122: 139–45.
Legoux R, Delpech B, Dumont X, Guillemot JC, Ramond P, Shire D, et al. Cloning and expression in Escherichia coli of the gene encoding Aspergillus flavus urate oxidase. J Biol Chem 1992; 267: 8565–70.
Luo X, Cai N, Cheng Z . Determination of uric acid in plasma by LC-MS/MS and its application to an efficacy evaluation of recombinant urate oxidase. Anal Sci 2013; 29: 709–13.
Luo X, Cai NF, Cheng ZN . Development of a new LC-MS/MS based enzyme activity assay for recombinant urate oxidase in plasma and its application to pharmacokinetics in human. J Pharm Biomed Anal 2013; 81–82: 8–12.
Zhu L, Wang QM, Wu GD, Xue TT, Sun LX, Wang JY . Expression, purification and activity identification of urate oxidase in Escherichia coli. China Biotechnol 2011; 31: 83–6.
Ishizawa K, Ogura M, Hamaguchi M, Hotta T, Ohnishi K, Sasaki T, et al. Safety and efficacy of rasburicase (SR29142) in a Japanese phase II study. Cancer Sci 2009; 100: 357–62.
Acknowledgements
The research was founded by the National Natural Science Foundation of China (No 81072700). In addition, we gratefully thank Shuang YANG, An YAO, and Lan-ni LI for gathering the biological samples.
Author information
Authors and Affiliations
Corresponding author
Additional information
(Supplementary figures are available at Acta Pharmacologica Sinica's website.
Supplementary information
PowerPoint slides
Rights and permissions
About this article
Cite this article
Cai, Nf., Cheng, Zn., Zi, Y. et al. Pharmacodynamic analysis of intravenous recombinant urate oxidase using an indirect pharmacological response model in healthy subjects. Acta Pharmacol Sin 35, 1447–1452 (2014). https://doi.org/10.1038/aps.2014.81
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2014.81
Keywords
This article is cited by
-
Pharmacokinetics of Polyethylene Glycol-Modified Canine Uricase Following Single and Multiple Intravenous Injections in Cynomolgus Monkeys
European Journal of Drug Metabolism and Pharmacokinetics (2020)
