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

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.