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

作者：Wright Daniel F B^*; Doogue Matthew P; Barclay Murray L; Chapman Peter T; Cross Nicholas B; Irvine John H; Stamp Lisa K

来源：European Journal of Clinical Pharmacology, 2017, 73(1): 71-78.

DOI：10.1007/s00228-016-2133-y

• Oxypurinol
• Population pharmacokinetics
• Dialysis
• Renal function
• NONMEM
• Gout

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.
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)).
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 mu mol/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 mu mol/L h). Dosing pre-dialysis resulted in about a 25-35 % reduction in exposure compared to post-dialysis.
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 ae0.36 mmol/L), then allopurinol doses may be increased to optimise oxypurinol exposure.

• 出版日期2017-1