title: Pharmacodynamic analysis of intravenous recombinant urate oxidase using an indirect pharmacological response model in healthy subjects.
abstract: OBJECTIVE
  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 (r(2)=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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 1] Department of Pharmacy, Zhangzhou Municipal Hospital of Fujian Province, Zhangzhou 363000, China [2] School of Pharmaceutical Sciences, Central South University, Changsha 410013, China.
authors.forename: Ning-fang
authors.initials: NF
authors.lastname: Cai
authors.affiliation: School of Pharmaceutical Sciences, Central South University, Changsha 410013, China.
authors.forename: Ze-neng
authors.initials: ZN
authors.lastname: Cheng
authors.affiliation: School of Pharmaceutical Sciences, Central South University, Changsha 410013, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zi
authors.affiliation: 1] School of Pharmaceutical Sciences, Central South University, Changsha 410013, China [2] School of Life Sciences, Central South University, Changsha 410013, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Luo
authors.affiliation: Hunan Tiger Xiangya Drug R&D Co, Ltd, Changsha 410013, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.affiliation: Hunan Tiger Xiangya Drug R&D Co, Ltd, Changsha 410013, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Central South University, Changsha 410013, China.
authors.forename: Li-yun
authors.initials: LY
authors.lastname: Zheng
mesh_terms: D002681:China; D054796:Drug Dosage Calculations; D005260:Female; D006074:Gout Suppressants / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008954:Models, Biological; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D065667:Renal Elimination; D016037:Single-Blind Method; D014503:Urate Oxidase / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D014527:Uric Acid / Q000097:blood / Q000652:urine; D055815:Young Adult
chemical_list: D006074:Gout Suppressants; D011994:Recombinant Proteins; D014527:Uric Acid; D014503:Urate Oxidase