The population pharmacokinetics of allopurinol and oxypurinol in patients with gout
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The aims of this study were to develop a population pharmacokinetic model for allopurinol and oxypurinol and to explore the influence of patient characteristics on allopurinol and oxypurinol pharmacokinetics.
Data from 92 patients with gout and 12 healthy volunteers were available for analysis. A parent–metabolite model with a two-compartment model for allopurinol and a one-compartment model for oxypurinol was fitted to the data using non-linear mixed effects modelling.
Renal function, fat-free mass (FFM) and diuretic use were found to predict differences in the pharmacokinetics of oxypurinol. The population estimates for allopurinol clearance, inter-compartmental clearance, central and peripheral volume were 50, 142 L/h/70 kg FFM, 11.4, 91 L/70 kg FFM, respectively, with a between-subject variability of 33 % (coefficient of variance, CV) for allopurinol clearance. Oxypurinol clearance and volume of distribution were estimated to be 0.78 L/h per 6 L/h creatinine clearance/70 kg FFM and 41 L/70 kg FFM in the final model, with a between-subject variability of 28 and 15 % (CV), respectively.
The pharmacokinetic model provides a means of predicting the allopurinol dose required to achieve target oxypurinol plasma concentrations for patients with different magnitudes of renal function, different body mass and with or without concomitant diuretic use. The model provides a basis for the rational dosing of allopurinol in clinical practice.
KeywordsAllopurinol Oxypurinol Population pharmacokinetics Renal function NONMEM Gout
At the time of writing, Dan Wright was the recipient of a University of Otago PhD scholarship. We wish to thank Dr. Rebecca Roberts, Department of Surgical Sciences, University of Otago, Dunedin for generous assistance with the AOX1 and MOCOS genotypes. We are also grateful to Jill Drake, Department of Rheumatology, Immunology and Allergy, Christchurch Hospital, for valuable assistance with the Christchurch data.
Conflicts of interest
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