Hishe Hailemichael Z, Stocker Sophie L, Stamp Lisa K, Dalbeth Nicola, Merriman Tony R, Wright Daniel F B
School of Pharmacy, University of Otago, Dunedin, New Zealand.
Pumas-AI Inc., DE.
Ther Drug Monit. 2025 Apr 1;47(2):281-288. doi: 10.1097/FTD.0000000000001265. Epub 2024 Nov 6.
Allopurinol dose reduction proportional to creatinine clearance (CLcr) results in suboptimal urate lowering in patients with gout. Similarly, diuretic therapy reduces oxypurinol clearance but is unexpectedly associated with the need for higher allopurinol doses to achieve the serum urate target (<0.36 mmol/L). The authors aimed to clarify the relationship between oxypurinol exposure and urate-lowering response in patients with gout at different stages of chronic kidney disease and those taking diuretics to determine the implications for maintenance dose selection.
Oxypurinol and urate data from 5 clinical studies were available. Model-derived steady-state oxypurinol areas under the concentration-time curves (AUCss 0-tau ) were estimated using a Bayesian methodology. The observed response metrics included the percentage reduction in urate from baseline and achievement of the target urate level. Exposure-response was explored graphically and using logistic regression. In addition, the influence of chronic kidney disease and diuretic use on the allopurinol dose and oxypurinol AUCss 0-tau requirements to achieve the serum urate target were explored.
Data from 258 patients with gout taking allopurinol representing 1288 paired steady-state oxypurinol and serum urate measurements were available. Higher oxypurinol exposure seems to be required for urate-lowering response normalization and achieve the serum urate target in individuals with reduced kidney function and those taking diuretics. However, allopurinol dose requirements were reduced by 2-fold at the extremes of kidney function and unchanged in those taking or not taking diuretics.
A lower allopurinol maintenance dose was required in patients with reduced kidney function (CLcr <30 mL/min), but this was not proportional to CLcr. Diuretic therapy did not influence allopurinol dose requirements.
根据肌酐清除率（CLcr）降低别嘌醇剂量会导致痛风患者尿酸降低效果欠佳。同样，利尿剂治疗会降低氧嘌呤醇清除率，但出人意料的是，这与需要更高剂量的别嘌醇才能达到血清尿酸目标（<0.36 mmol/L）有关。作者旨在阐明慢性肾脏病不同阶段的痛风患者以及服用利尿剂的患者中氧嘌呤醇暴露与尿酸降低反应之间的关系，以确定维持剂量选择的意义。
有来自5项临床研究的氧嘌呤醇和尿酸数据。使用贝叶斯方法估算模型推导的稳态下氧嘌呤醇浓度-时间曲线下面积（AUCss 0-tau）。观察到的反应指标包括尿酸较基线水平降低的百分比以及达到目标尿酸水平的情况。通过图形和逻辑回归探索暴露-反应关系。此外，还探讨了慢性肾脏病和利尿剂使用对达到血清尿酸目标所需的别嘌醇剂量和氧嘌呤醇AUCss 0-tau的影响。
有来自258例服用别嘌醇的痛风患者的数据，代表1288对稳态氧嘌呤醇和血清尿酸测量值。对于肾功能减退和服用利尿剂的个体，似乎需要更高的氧嘌呤醇暴露才能使尿酸降低反应正常化并达到血清尿酸目标。然而，在肾功能极差时，别嘌醇剂量需求降低了2倍，而服用或未服用利尿剂的患者中别嘌醇剂量需求没有变化。
肾功能减退（CLcr<30 mL/min）的患者需要较低的别嘌醇维持剂量，但这与CLcr不成比例。利尿剂治疗不影响别嘌醇剂量需求。
