Untangling the Exposure-Response Relationship of Allopurinol in the Setting of Chronic Kidney Disease and Diuretic Use: Implications for Dosing.

IF 2.8 4区 医学 Q2 MEDICAL LABORATORY TECHNOLOGY Therapeutic Drug Monitoring Pub Date : 2024-11-06 DOI:10.1097/FTD.0000000000001265
Hailemichael Z Hishe, Sophie L Stocker, Lisa K Stamp, Nicola Dalbeth, Tony R Merriman, Daniel F B Wright
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Abstract

Background: 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.

Methods: Oxypurinol and urate data from 5 clinical studies were available. Model-derived steady-state oxypurinol areas under the concentration-time curves (AUCss0-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 AUCss0-tau requirements to achieve the serum urate target were explored.

Results: 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.

Conclusions: 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.

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在慢性肾脏病和使用利尿剂的情况下解开别嘌醇的暴露-反应关系:对剂量的影响。
背景:别嘌醇剂量减少与肌酐清除率(CLcr)成正比会导致痛风患者尿酸盐降低效果不理想。同样,利尿剂治疗可降低别嘌醇清除率,但却意外地与需要更高的别嘌醇剂量以达到血清尿酸盐目标值有关(方法:从 5 个临床试验中获得的别嘌醇和尿酸盐数据:从 5 项临床研究中获得了羟嘌呤醇和尿酸盐的数据。采用贝叶斯方法估算了模型推导的稳态别嘌醇浓度-时间曲线下面积(AUCss0-tau)。观察到的反应指标包括尿酸盐从基线降低的百分比和达到目标尿酸盐水平。通过图表和逻辑回归对暴露-反应进行了探讨。此外,还探讨了慢性肾病和使用利尿剂对实现血清尿酸目标所需的别嘌呤醇剂量和氧嘌呤醇 AUCss0-tau 的影响:258 名服用别嘌醇的痛风患者的数据代表了 1288 次成对的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患者,似乎需要更高的别嘌醇暴露量才能使降尿酸反应正常化并达到血清尿酸目标值。然而,在肾功能极差的情况下,别嘌醇的剂量需求降低了 2 倍,而在服用或未服用利尿剂的情况下,别嘌醇的剂量需求保持不变:结论:肾功能减退(CLcr
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来源期刊
Therapeutic Drug Monitoring
Therapeutic Drug Monitoring 医学-毒理学
CiteScore
5.00
自引率
8.00%
发文量
213
审稿时长
4-8 weeks
期刊介绍: Therapeutic Drug Monitoring is a peer-reviewed, multidisciplinary journal directed to an audience of pharmacologists, clinical chemists, laboratorians, pharmacists, drug researchers and toxicologists. It fosters the exchange of knowledge among the various disciplines–clinical pharmacology, pathology, toxicology, analytical chemistry–that share a common interest in Therapeutic Drug Monitoring. The journal presents studies detailing the various factors that affect the rate and extent drugs are absorbed, metabolized, and excreted. Regular features include review articles on specific classes of drugs, original articles, case reports, technical notes, and continuing education articles.
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