Allopurinol: insights from studies of dose–response relationships

ABSTRACT

Introduction: Gout is the most common inflammatory arthritis in men and is increasingly prevalent. Allopurinol is very effective at reducing plasma urate concentrations to a level sufficient to dissolve monosodium urate crystals. However, many patients fail to achieve a sufficient therapeutic response to allopurinol.

Areas covered: This review covers the metabolism and pharmacokinetics of allopurinol and its active metabolite, oxypurinol and how these factors affect the plasma concentrations of urate at initiation and during long-term therapy with allopurinol. Significant aspects discussed are the importance of adherence to allopurinol therapy, allopurinol hypersensitivity reactions and insights into hyperuricemia.

Expert opinion: The initial dosage of allopurinol should be low, particularly in patients with renal impairment. The dose should then be increased slowly until plasma concentrations of urate are sufficient to dissolve monosodium urate crystals (≤ 0.36 mmol/L). For this target, the maintenance dose of allopurinol can be estimated from the equation: Dose = 1413*(U_p-0.36) where U_p is the pre-treatment concentration of urate. Poor adherence is a major factor limiting successful therapy with allopurinol; however, its use can be improved considerably by education of patients and clinicians. Allopurinol is generally well tolerated and screening for genetic factors predictive of allopurinol hypersensitivity reactions can now be undertaken.

KEYWORDS:

• Gout
• xanthine oxidoreductase
• uric acid
• adherence
• allopurinol
• hyperuricemia
• allopurinol hypersensitivity

Article highlights

• Gout is prevalent and increasingly so globally

• Gout attacks and urate crystal deposits can be eliminated if plasma urate concentrations are maintained below well established target concentrations

• XOR inhibition has potential therapeutic efficacy beyond the prevention of recurrent gout

• The long-term consequences of lowered plasma urate concentrations beyond gout treatment require elucidation

• ULT dosing rates are most influenced by the baseline urate concentration, higher concentrations requiring higher doses of ULT for XOR inhibition

• Dealing with adherence to the critical need for daily XOR inhibitory pharmacotherapy is the major impediment to control of gout but allopurinol remains the first choice ULT

This box summarizes key points contained in the article.

Declaration of interest

RO Day and KM Williams are Investigators on an NH&MRC Partnership Grant (#1094708; 2015-16) investigating whether response rates to urate lowering therapy can be increased in primary care. Menarini Australia (makers of febuxostat) and AstraZeneca Pty Ltd (makers of lesinurad) are two of seven partners, the rules for avoidance of conflicts of interest being clearly stated by NH&MRC. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.