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

Eur J Clin Pharmacol. 2017 Jan;73(1):71-78. doi: 10.1007/s00228-016-2133-y. Epub 2016 Sep 28.

Abstract

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 (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 AUC7days of 279 μmol/L h in dialysis patients, a value 50-75 % lower than the AUC7days 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.

Keywords: Dialysis; Gout; NONMEM; Oxypurinol; Population pharmacokinetics; Renal function.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Allopurinol / blood
  • Allopurinol / pharmacokinetics*
  • Female
  • Gout / blood
  • Gout / drug therapy
  • Gout / metabolism
  • Gout Suppressants / blood
  • Gout Suppressants / pharmacokinetics*
  • Humans
  • Male
  • Middle Aged
  • Models, Biological*
  • Oxypurinol / blood*
  • Renal Dialysis*

Substances

  • Gout Suppressants
  • Allopurinol
  • Oxypurinol