The pharmacokinetics of oxypurinol in people with gout.
OBJECTIVE
Our aim was to identify and quantify the sources of variability in oxypurinol pharmacokinetics and explore relationships with plasma urate concentrations.


METHODS
Non-linear mixed effects modelling was applied to concentration-time data from 155 gouty patients with demographic, medical history and renal transporter genotype information.


RESULTS
A one compartment pharmacokinetic model with first order absorption best described the oxypurinol concentration-time data. Renal function and concomitant medicines (diuretics and probenecid), but not transporter genotype, significantly influenced oxypurinol pharmacokinetics and reduced the between subject variability in the apparent clearance of oxypurinol (CL/F(m)) from 65% to 29%. CL/F(m) for patients with normal, mild, moderate and severe renal impairment was 1.8, 0.6, 0.3 and 0.18 l h(-1), respectively. Model predictions showed a relationship between plasma oxypurinol and urate concentrations and failure to reach target oxypurinol concentrations using suggested allopurinol dosing guidelines.


CONCLUSIONS
In conclusion, this first established pharmacokinetic model provides a tool to achieve target oxypurinol plasma concentrations, thereby optimizing the effectiveness and safety of allopurinol therapy in gouty patients with various degrees of renal impairment.
Faculty of Pharmacy, University of Sydney, NSW, Australia.
Sophie L
SL
Stocker
Andrew J
AJ
McLachlan
Radojka M
RM
Savic
Carl M
CM
Kirkpatrick
Garry G
GG
Graham
Kenneth M
KM
Williams
Richard O
RO
Day
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004232:Diuretics / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D005260:Female; D006073:Gout / Q000503:physiopathology*; D006074:Gout Suppressants / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010117:Oxypurinol / Q000493:pharmacokinetics*; D011339:Probenecid / Q000494:pharmacology; D051437:Renal Insufficiency / Q000503:physiopathology*; D012720:Severity of Illness Index
D004232:Diuretics; D004791:Enzyme Inhibitors; D006074:Gout Suppressants; D010117:Oxypurinol; D011339:Probenecid