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Pharmacodynamic analysis of intravenous recombinant urate oxidase using an indirect pharmacological response model in healthy subjects . 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 ( 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 . 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 .
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Intervention_Pharmacological
intravenous recombinant urate oxidase
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Intervention_Pharmacological
intravenous recombinant urate oxidase
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Intervention_Control
placebo-controlled
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Intervention_Pharmacological
uricase
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Participant_Condition
indirect pharmacological response model in healthy subjects .
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Participant_Condition
healthy
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Participant_Condition
pharmacokinetic/pharmacodynamic
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Participant_Sample-size
40
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Participant_Condition
healthy