Relative Forgiveness of Different Allopurinol Implementation Patterns in People with Gout and their Impact on Clinical Outcomes: a Simulation Study

Background and Objective: 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. Methods: A simulation study was conducted using a pharmacokinetic–pharmacodynamic model for allopurinol and serum urate to determine the RF of allopurinol implementation patterns. Results: 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. Conclusion: 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.