A population pharmacokinetic model to predict oxypurinol exposure in patients on haemodialysis
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 (AUC7days).
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.
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.
KeywordsOxypurinol Population pharmacokinetics Dialysis Renal function NONMEM Gout
We are grateful to Professor Stephen Duffull for his help with the population analysis and for reviewing the final manuscript. We thank Jill Drake, Megan Gath, and Janine Francis, Department of Rheumatology, Immunology and Allergy, Christchurch Hospital, who provided valuable assistance with data collection. We thank Dr. Mei Zhang, Canterbury Health Laboratories, for her work with the oxypurinol assay. We wish to thank Nele Plock for her assistance with the VSLOPE code. The ‘allopurinol starter’ study was funded by a University of Otago Research’ Grant. The ‘dialysis study’ was funded by the Ross Bailey Nephrology Trust.
Contribution of authors
D.F.B.W., M.P.D., M.L.B., P.T.C., N.B.C., and L.K.S wrote the manuscript. L.K.S., M.P.D., M.L.B., P.T.C., N.B.C., and J.H.I. designed the ‘dialysis study’. D.F.B.W., M.L.B., P.T.C., and L.K.S designed the ‘allopurinol starter study’. L.K.S., M.P.D., M.L.B., P.T.C., N.B.C., and J.H.I. collected the data. L.K.S, M.P.D, and P.T.C conceived of the research. D.F.B.W. conducted the population analysis.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
This article does not contain any studies with animals performed by any of the authors.
Informed consent was obtained from all individual participants included in the study.
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