Premium
Uricases as Therapeutic Agents to Treat Refractory Gout: Current States and Future Directions
Author(s) -
Yang Xiaolan,
Yuan Yonghua,
Zhan ChangGuo,
Liao Fei
Publication year - 2012
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.20493
Subject(s) - refractory (planetary science) , gout , medicine , current (fluid) , intensive care medicine , pharmacology , engineering , physics , astrobiology , electrical engineering
trategy, Management and Health PolicyEnabling Technology, Genomics, Proteomics Preclinical Research Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics Clinical Development Phases I‐III Regulatory, Quality, Manufacturing Postmarketing Phase IVTreatment of refractory gout remains a challenge on drug development. While pegloticase, a recombinant mammalian uricase modified with monomethoxyl poly(ethylene glycol) ( mPEG ) is effective in treating refractory gout, after continued treatment for 3 months biweekly at a therapeutic dose of 0.14 mg/kg body weight, it elicits an immune response against mPEG in nearly 20% of patients. For continued treatment of refractory gout, PEG ylated uricases at monthly therapeutic doses below 4 μg/kg body weight have promise. To formulate uricases to achieve monthly therapeutic regimens requires pharmacodynamics simulation and experimentation including molecular engineering of uricases based on rational design and evolution biotechnology in combination to improve their inherent catalytic efficiency, thermostability and selectivity for urate over xanthine and optimization of the number and distribution of accessible reactive amino acid residues in native uricases for site‐specific PEG ylation with poly(ethylene glycol) derivatives with lower of immunogenicity than mPEG to retain activity, minimize immunogenicity and enhance the pharmacokinetics of the PEGylated uricase. These issues are briefly reviewed as a means to stimulate the development of safer uricase formulations for continued treatment of refractory gout.