A population pharmacokinetic model to predict oxypurinol exposure in patients on haemodialysis.
OBJECTIVE
The aims of this study were to characterise the population pharmacokinetics of oxypurinol in patients receiving haemodialysis and to compare oxypurinol exposure in dialysis and non-dialysis patients.


METHODS
Oxypurinol plasma concentrations from 6 gout people receiving haemodialysis and 19 people with gout not receiving dialysis were used to develop a population pharmacokinetic model in NONMEM. Deterministic simulations were used to predict the steady-state area under the oxypurinol plasma concentration time curve over 1 week (AUC7days).


RESULTS
The pharmacokinetics of oxypurinol were best described by a one-compartment model with a separate parameter for dialytic clearance. Allopurinol 100 mg daily produced an AUC7daysof 279 μmol/L h in dialysis patients, a value 50-75 % lower than the AUC7dayspredicted for patients with normal renal function taking 200 to 400 mg daily (427-855 μmol/L h). Dosing pre-dialysis resulted in about a 25-35 % reduction in exposure compared to post-dialysis.


CONCLUSIONS
Oxypurinol is efficiently removed by dialysis. The population dialytic and total (non-dialytic) clearance of oxypurinol were found to be 8.23 and 1.23 L/h, standardised to a fat-free mass of 70 kg and creatinine clearance of 6 L/h, respectively. Our results suggest that if the combination of low-dose allopurinol and haemodialysis does not result in sustained urate lowering below treatment targets (serum urate ≤0.36 mmol/L), then allopurinol doses may be increased to optimise oxypurinol exposure.
School of Pharmacy, University of Otago, PO Box 56, Dunedin, 9054, New Zealand. dan.wright@otago.ac.nz.
Daniel Fb
DF
Wright
Department of Medicine, University of Otago, Christchurch, New Zealand.|Department of Clinical Pharmacology, Christchurch Hospital, Christchurch, New Zealand.
Matthew P
MP
Doogue
Department of Medicine, University of Otago, Christchurch, New Zealand.|Department of Clinical Pharmacology, Christchurch Hospital, Christchurch, New Zealand.
Murray L
ML
Barclay
Department of Medicine, University of Otago, Christchurch, New Zealand.|Department of Rheumatology Immunology and Allergy, Christchurch Hospital, Christchurch, New Zealand.
Peter T
PT
Chapman
Department of Medicine, University of Otago, Christchurch, New Zealand.
Nicholas B
NB
Cross
Department of Medicine, University of Otago, Christchurch, New Zealand.
John H
JH
Irvine
Department of Medicine, University of Otago, Christchurch, New Zealand.|Department of Rheumatology Immunology and Allergy, Christchurch Hospital, Christchurch, New Zealand.
Lisa K
LK
Stamp
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000493:Allopurinol / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006073:Gout / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D006074:Gout Suppressants / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010117:Oxypurinol / Q000097:blood*; D006435:Renal Dialysis
D006074:Gout Suppressants; D000493:Allopurinol; D010117:Oxypurinol
Dialysis; Gout; NONMEM; Oxypurinol; Population pharmacokinetics; Renal function
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