Population Pharmacokinetic and Pharmacodynamic Analysis of Pegloticase in Subjects With Hyperuricemia and Treatment‐Failure Gout

Yue, Corinne Seng; Huang, Wen; Alton, Michelle; Maroli, Allan N.; Waltrip, Royce W.; Wright, David; Marco, M. Di

doi:10.1177/0091270008317589

Cited by 25 publications

(27 citation statements)

References 13 publications

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“…It has also been administered to a small number of patients after stroke (29) and in an individual with the Lesch-Nyhan syndrome (30). In patients with gout, recombinant urate oxidase (26) and chemically modified preparations of recombinant urate oxidase with a prolonged half-life (27,31) have been used for up to 6 mo in clinical trials. These patients demonstrate prolonged biochemical evidence of uric acid breakdown, and some patients appeared to derive clinical benefit from this therapy (23).…”

Section: Discussionmentioning

confidence: 99%

Deficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice

Stevenson

Hyland²,

Zhang³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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With the notable exception of humans, uric acid is degraded to (S)-allantoin in a biochemical pathway catalyzed by urate oxidase, 5-hydroxyisourate (HIU) hydrolase, and 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline decarboxylase in most vertebrate species. A point mutation in the gene encoding mouse HIU hydrolase, Urah, that perturbed uric acid metabolism within the liver was discovered during a mutagenesis screen in mice. The predicted substitution of cysteine for tyrosine in a conserved helical region of the mutantencoded HIU hydrolase resulted in undetectable protein expression. Mice homozygous for this mutation developed elevated platelet counts secondary to excess thrombopoietin production and hepatomegaly. The majority of homozygous mutant mice also developed hepatocellular carcinoma, and tumor development was accelerated by exposure to radiation. The development of hepatomegaly and liver tumors in mice lacking Urah suggests that uric acid metabolites may be toxic and that urate oxidase activity without HIU hydrolase function may affect liver growth and transformation. The absence of HIU hydrolase in humans predicts slowed metabolism of HIU after clinical administration of exogenous urate oxidase in conditions of uric acid-related pathology. The data suggest that prolonged urate oxidase therapy should be combined with careful assessment of toxicity associated with extrahepatic production of uric acid metabolites.N-ethyl-N-nitrosourea mutagenesis | uric acid | 5-hydroxyisourate hydrolase | hepatocellular carcinoma | thrombopoietin U ric acid is the product of purine metabolism. In most mammals, uric acid, or urate, the form that predominates in vivo, is further metabolized to (S)-allantoin (1, 2). In humans and some higher primates, the urate oxidase gene is dysfunctional because of the introduction of premature stop codons during recent evolution (3). A nonfunctional urate oxidase enzyme causes a relative excess of uric acid in humans compared with most other vertebrate species. Because uric acid is relatively insoluble, humans are susceptible to diseases resulting from precipitation of uric acid such as gout and kidney stones as well as urate nephropathy associated with the tumor lysis syndrome. Chronic hyperuricemia in humans has also been linked to the development of cardiovascular disease and hypertension (4, 5).It is unclear why humans have evolved this block in uric acid metabolism during evolution, but suggested theoretical advantages of increased levels of circulating uric acid include its role as a potent antioxidant offering protection from cancer and aging (6) and its potential function in maintenance of adequate blood pressure during periods of low salt intake (7).The components of the full metabolic pathway that converts urate to allantoin in lower mammals have only recently been identified (1). Although it was originally thought that urate oxidase was the sole enzymatic component of this pathway, recent studies have established that conversion of uric acid to allantoin occurs by sequential ch...

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Section: Discussionmentioning

confidence: 99%

Deficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice

Stevenson

Hyland²,

Zhang³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Because there were no detectable uricase activities in plasma from healthy rats, it was simple to determine the half-life time of a uricase formulation in vivo in healthy rats by monitoring changes of its activities in plasma. A mammalian uricase after modification with poly(ethylene glycol) (PEG) followed one-compartment pharmacokinetics in human plasma in vivo Yue et al, 2008). It is possible that there was a large difference in the half-life time of uricase before and after modification with mPEG5k.…”

Section: Discussionmentioning

confidence: 99%

“…After repetitive injection of uricase formulations, specific immune responses may play important roles in their clearance in vivo. A mammalian uricase after modification with a long-chain mPEG still showed a half-life of about 3 d in vivo in human body after the first administration Yue et al, 2008). Usually the modification of a protein with longchain mPEG can produce a longer half-life in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…From the modeled pharmacodynamics, the roles of different properties of uricase formulations in their pharmacological significance to maintain desired levels of plasma uric acid for a required duration can be understood more clearly (Danhof et al, 2007(Danhof et al, , 2008Yue et al, 2008). Taken together, our practical system, which is based on (1) the ability of uricase formulations to eliminate uric acid from plasma in vitro, (2) the pharmacokinetics of uricase formulations in vivo in healthy animals, and (3) the modeled pharmacodynamics in vivo, is associated with much lower cost and greater efficiency for preliminary screening of formulations of engineered uricases as potential drugs to handle hyperuricemia.…”

Section: Discussionmentioning

confidence: 99%

“…The principal determinants of the pharmacological significance of a uricase as a drug include its ability to eliminate uric acid from plasma, its half-life, and its immunogenicity, all in vivo (Jeha et al, 2005;Bertrand et al, 2008;Biggers and Scheinfeld, 2008;Sherman et al, 2008;Yue et al, 2008). Uricases usually have an optimum pH over 8.5, and these enzymes thus invariably exhibit low activities in plasma of neutral pH (Bomalaski et al, 2002;Zhao et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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A new practical system for evaluating the pharmacological properties of uricase as a potential drug for hyperuricemia

Feng

Yang

et al. 2010

Arch. Pharm. Res.

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The use of uricase-deficient mammals to screen formulations of engineered uricases as potential drugs for hyperuricemia involves heavy costs and presents a technical bottleneck. Herein, a new practical system was investigated to evaluate the pharmacological significance of a bacterial uricase based on its ability to eliminate uric acid in plasma in vitro, its pharmacokinetics in vivo in healthy rats, and the modeled pharmacodynamics in vivo. This uricase, before and after modification with the monomethyl ether of poly(ethylene glycol)-5000, effectively eliminated uric acid in vitro in rabbit plasma, but its action was susceptible to xanthine inhibition. After intravenous injection of the modified uricase without purification, a bi-exponential model fit well to uricase activities in vivo in the plasma of healthy rats; the half-life of the modified uricase was estimated without interference from the unmodified uricase leftover in the sample and was nearly 100-fold longer than that of the unmodified uricase. Using a model of the elimination of uric acid in vivo taking into account of uricase pharmacokinetics and xanthine inhibition, modeled pharmacodynamics supported that the half-life of uricase and its susceptibility to xanthine are crucial for the pharmacological significance of uricase. Hence, this practical system is desirable for doing preliminary screening of formulations of engineered uricases as potential drugs for hyperuricemia.

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Pegloticase for chronic gout

Anderson¹,

Noorbaloochi²,

Singh³

2010

Cochrane Database of Systematic Reviews

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Population Pharmacokinetic and Pharmacodynamic Analysis of Pegloticase in Subjects With Hyperuricemia and Treatment‐Failure Gout

Cited by 25 publications

References 13 publications

Deficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice

Deficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice

A new practical system for evaluating the pharmacological properties of uricase as a potential drug for hyperuricemia

Pegloticase for chronic gout

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