White-Koning Melanie, Wright Daniel F B, Hughes Dyfrig A, Michael Toni J F, Coleshill Matthew J, Aslani Parisa, Day Richard O, Stocker Sophie L
Cancer Research Center of Toulouse (CRCT), Inserm U1037, Université Paul Sabatier, Toulouse, France.
Sydney Pharmacy School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
Clin Pharmacokinet. 2025 Jan;64(1):93-105. doi: 10.1007/s40262-024-01467-z. Epub 2024 Dec 18.
Adherence to urate-lowering therapy among people with gout is poor, so it is important to understand which day-to-day medication-taking ('implementation') patterns are most likely to lead to suboptimal serum urate concentrations and worsen clinical outcomes. This study aimed to (1) determine the relative forgiveness (RF) of allopurinol with hypothetical and real-life implementation patterns in people with gout, (2) explore the use of RF as a means of identifying suboptimal implementation patterns, (3) assess the impact of suboptimal implementation patterns on clinical outcomes.
A simulation study was conducted using a pharmacokinetic-pharmacodynamic model for allopurinol and serum urate to determine the RF of allopurinol implementation patterns.
With 100% ('perfect') implementation, the probability of adequate urate control (> 90% of days with urate < 0.36 mmol/L over 360 days) for a 300 mg dose of allopurinol was 0.549. Simulations based on real-life individual implementation patterns over a year yielded a median RF of 0.51, indicating that half of the patterns studied were at least 50% less likely to achieve adequate urate control than perfect implementation.
Our study provides evidence that missing one or two doses of allopurinol, even repeatedly over a year, does not significantly impact serum urate target achievement or clinical outcomes. However, people who take repeated drug holidays of more than 3 days in a row (followed by less than 15 consecutive days of dosing) are less than 0.3 times as likely (at least 70% less likely) to achieve adequate urate control than those with perfect implementation and may see an increase in the frequency of gout flares.
痛风患者对降尿酸治疗的依从性较差，因此了解哪种日常服药（“实施”）模式最有可能导致血清尿酸盐浓度未达最佳水平并使临床结局恶化至关重要。本研究旨在：（1）确定痛风患者中别嘌醇在假设和实际服药模式下的相对宽容度（RF）；（2）探索将RF作为识别次优服药模式的一种方法；（3）评估次优服药模式对临床结局的影响。
使用别嘌醇和血清尿酸盐的药代动力学 - 药效学模型进行模拟研究，以确定别嘌醇服药模式的RF。
在100%（“完美”）服药的情况下，300mg剂量别嘌醇实现尿酸盐充分控制（360天内尿酸盐<0.36mmol/L的天数>90%）的概率为0.549。基于一年中实际个体服药模式的模拟得出RF中位数为0.51，这表明所研究的模式中有一半实现尿酸盐充分控制的可能性比完美服药模式至少低50%。
我们的研究提供了证据，表明漏服一剂或两剂别嘌醇，即使在一年中反复出现，也不会显著影响血清尿酸盐目标的实现或临床结局。然而，连续多次停药超过3天（随后连续给药少于15天）的患者实现尿酸盐充分控制的可能性比完美服药的患者低至0.3倍（至少低70%），并且痛风发作频率可能会增加。
