Pharmacodynamic analysis of intravenous recombinant urate oxidase using an indirect pharmacological response model in healthy subjects
Abstract
Ning-fang CAI1, 2, Ze-neng CHENG2, Ying ZI2, Xi LUO2, 3, *, Xin GUO4, Zhi LIU4, Li-yun ZHENG2
1Department of Pharmacy, Zhangzhou Municipal Hospital of Fujian Province, Zhangzhou 363000, China; 2School of Pharmaceutical Sciences, Central South University, Changsha 410013, China; 3School of Life Sciences, Central South University, Changsha 410013, China; 4Hunan Tiger Xiangya Drug R&D Co, Ltd, Changsha 410013, China
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.
Keywords: recombinant urate oxidase; uric acid; pharmacokinetic and pharmacodynamic model; safety
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.
* To whom correspondence should be addressed.
E-mail luoxi2999@163.com
Received 2014-01-29 Accepted 2014-08-11
Keywords:
1Department of Pharmacy, Zhangzhou Municipal Hospital of Fujian Province, Zhangzhou 363000, China; 2School of Pharmaceutical Sciences, Central South University, Changsha 410013, China; 3School of Life Sciences, Central South University, Changsha 410013, China; 4Hunan Tiger Xiangya Drug R&D Co, Ltd, Changsha 410013, China
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.
Keywords: recombinant urate oxidase; uric acid; pharmacokinetic and pharmacodynamic model; safety
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.
* To whom correspondence should be addressed.
E-mail luoxi2999@163.com
Received 2014-01-29 Accepted 2014-08-11