Open AccessRelationships Between Allopurinol Dose, Oxypurinol Concentration and Urate‐Lowering Response—In Search of a Minimum Effective Oxypurinol Concentration
Author(s) -
Stamp Lisa K.,
Chapman Peter T.,
Barclay Murray,
Horne Anne,
Frampton Christopher,
Merriman Tony R.,
Wright Daniel F. B.,
Drake Jill,
Dalbeth Nicola
Publication year - 2020
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/cts.12686
Subject(s) - allopurinol , uric acid , pharmacology , medicine , creatinine , receiver operating characteristic , area under the curve , renal function , chemistry , urology
The aims of this study were to determine factors that predict serum urate ( SU ) lowering response to allopurinol and the conversion of allopurinol to oxypurinol, and to determine a minimum therapeutic oxypurinol concentration. Data from 129 participants in a 24‐month open, randomized, controlled, parallel‐group, comparative clinical trial were analyzed. Allopurinol dose, SU, and plasma oxypurinol concentrations were available at multiple time points. The slope for the association between allopurinol dose and SU was calculated as a measure of sensitivity to allopurinol. The slope for the association between allopurinol dose and oxypurinol was calculated as a measure of allopurinol metabolism. Receiver operating characteristic ( ROC ) curves were used to identify a minimum oxypurinol concentration predictive of SU < 6 mg/dL. There was a wide range of SU concentrations for each allopurinol dose. The relationship between sensitivity to allopurinol and allopurinol metabolism for each 100 mg allopurinol dose increase varied between individuals. Body mass index ( P = 0.023), creatinine clearance (Cr CL ; P = 0.037), ABCG2 Q141K ( P = 0.019), and SU ( P = 0.004) were associated with sensitivity to allopurinol. The minimum oxypurinol concentration for achieving the urate target was found to be about 104 μmol/L, but predictive accuracy was poor ( ROC curve area under the curve ( AUC ) 0.65). The minimum therapeutic oxypurinol concentration was found to increase with decreasing renal function. Although there is a positive relationship between change in oxypurinol and change in SU concentration, a minimum therapeutic oxypurinol is dependent on Cr CL and cannot reliably predict SU target. Other variables, including ABCG 2 Q141K genotype, impact on sensitivity to allopurinol ( ACTRN 12611000845932).