Understanding the dose–response relationship of allopurinol: predicting the optimal dosage

Abstract

AIMSThe aim of the study was to identify and quantify factors that control the plasma concentrations of urate during allopurinol treatment and to predict optimal doses of allopurinol. METHODSPlasma concentrations of urate and creatinine (112 samples, 46 patients) before and during treatment with various doses of allopurinol (50-600 mg daily) were monitored. Non-linear and multiple linear regression equations were used to examine the relationships between allopurinol dose (D), creatinine clearance (CLcr) and plasma concentrations of urate before (UP) and during treatment with allopurinol (UT). RESULTSPlasma concentrations of urate achieved during allopurinol therapy were dependent on the daily dose of allopurinol and the plasma concentration of urate pre-treatment. The non-linear equation: ). Incorporation of CLcr did not significantly improve the fit (P = 0.09). CONCLUSIONSA high baseline plasma urate concentration requires a high dose of allopurinol to reduce plasma urate below recommended concentrations. This dose is dependent on only the pre-treatment plasma urate concentration and is not influenced by CLcr.

The Budget Impact of Increased Use of Febuxostat in the Management of Gout: A US Health Plan Managed Care Pharmacy and Medical Costs Perspective

“…8 AHS led to a renal clearance-based dosing algorithm, 31 which generally restricted ALLO dosing to levels ineffective for most patients. 32,33 Recent US guidelines have relaxed the dosing limitations on ALLO for patients, including those with renal impairment, provided there is adequate patient education and monitoring. 8 However, ALLO dosing 4300 mg/d is uncommon (o10% of ALLO patients), even given that o50% of patients treated with ALLO 300 mg/d achieve target sUA levels.…”

“…Recent studies have reported the benefits of ALLO titration to higher daily dosages. 33,58,59 No treatment-related adverse event costs, aside from those related to ALLO AHS, were included in the budget impact analysis. This was justified based on similar adverse event rates for FEBUX and ALLO from clinical trial data.…”

Allopurinol and kidney function: An update

“…Whether genetic variation in these genes also influences renal oxypurinol clearance and thus the clinical response, or lack of response to allopurinol, is the subject of current research. The recognition that serum urate prior to allopurinol therapy is a key determinant of allopurinol dose required to reach the target serum urate in gout [7] provides further evidence that genetic variants influencing urate may also have a role in allopurinol response to therapeutic interventions.…”

Pharmacokinetics considerations for gout treatments

“…Thus, the decrease in renal function leads to higher plasma concentration of oxypurinol but in turn does not lead to greater inhibition of XO. Indeed, greater inhibition of urate synthesis is required to counter the decreased urate clearance associated with renal impairment [41].…”

“…Dose adjustment of allopurinol according to creatinine clearance is controversial. It often does not allow for reaching the recommended urate target of 6 mg/dl [41,87]. In this case, the patient should be switched to another ULT, such as febuxostat.…”