The impact of diuretic use and ABCG2 genotype on the predictive performance of a published allopurinol dosing tool

Abstract

Aim: This research aims to evaluate the predictive performance of a published allopurinol dosing tool.

Methods: Allopurinol dose predictions were compared to the actual dose required to achieve serum urate (SU) <0.36 mmol l^-1 using mean prediction error. The influence of patient factors on dose predictions was explored using multilinear regression.

Results: Allopurinol doses were overpredicted by the dosing tool; however, this was minimal in patients without diuretic therapy (MPE 63 mg day^-1 , 95% CI 40-87) compared to those receiving diuretics (MPE 295 mg day^-1 , 95% CI 260-330, P < 0.0001). ABCG2 genotype (rs2231142, G>T) had an important impact on the dose predictions (MPE 201, 107, 15 mg day^-1 for GG, GT and TT, respectively, P < 0.0001). Diuretic use and ABCG2 genotype explained 53% of the variability in prediction error (R² = 0.53, P = 0.0004).

Conclusions: The dosing tool produced acceptable maintenance dose predictions for patients not taking diuretics. Inclusion of ABCG2 genotype and a revised adjustment for diuretics would further improve the performance of the dosing tool.

Keywords: ABCG2; allopurinol; diuretics; genotype; gout; urate.

Figure 1

Data plots for observed doses, predicted doses and prediction error. A: Relationship between the observed and predicted allopurinol maintenance doses. B: Relationship between the observed and predicted allopurinol maintenance doses in those with and without concomitant diuretics. C: Box plots of raw prediction error for each genotype of ABCG2 (rs2231142). Differences in prediction error between ABCG2 genotypes were assessed by ANOVA (P < 0.0001) and by t‐test, i.e. GG vs. GT (P = 0.007), GG vs. TT (P = 0.0002) and GT vs. TT (P = 0.05). D: Box plots of raw prediction error for each genotype of ABCG2 (rs2231142) in those with and without concomitant diuretics. Differences in prediction error between ABCG2 genotypes for those not taking diuretics were assessed by ANOVA (P = 0.0002) and by t‐test, i.e. GG vs. GT (P = 0.0001), GG vs. TT (P = 0.065), and, GT vs. TT (P = 0.0052). Differences in prediction error between ABCG2 genotypes for those taking diuretics were assessed by ANOVA (P = 0.0183) and by t‐test, i.e. GG vs. GT (P = 0.0432), GG vs. TT (P = 0.0188), and, GT vs. TT (P = 0.63). Differences in prediction error for those with and without concomitant diuretic therapy stratified by ABCG2 genotype was assessed by t‐test as follows; GG genotype no diuretic vs. diuretic (P < 0.0001), GT genotype no diuretic vs. diuretic (P < 0.001) and TT genotype no diuretic vs. diuretic (P = 0.0107)