A population pharmacokinetic model to predict oxypurinol exposure in patients on haemodialysis

• Published in: European journal of clinical pharmacology 2017, Vol.73 (1), p.71-78
• Main Authors: Wright, Daniel FB, Doogue, Matthew P., Barclay, Murray L, Chapman, Peter T, Cross, Nicholas B, Irvine, John H, Stamp, Lisa K
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Allopurinol - blood; Allopurinol - pharmacokinetics; Biomedical and Life Sciences; Biomedicine; Female; Gout - blood; Gout - drug therapy; Gout - metabolism; Gout Suppressants - blood; Gout Suppressants - pharmacokinetics; Hemodialysis; Humans; Kinetics; Male; Middle Aged; Models, Biological; Oxypurinol - blood; Pharmacokinetics and Disposition; Pharmacology; Pharmacology/Toxicology; Renal Dialysis; Studies
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-016-2133-y

Purpose 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 (AUC 7days ). 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 AUC 7days of 279 μmol/L h in dialysis patients, a value 50–75 % lower than the AUC 7days predicted 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.