Allopurinol dosing in patients with renal impairment

Background: Allopurinol is used to manage gout and works by reducing plasma urate concentrations. Daily doses recommended by the current renal dosing guidelines [1] fail to achieve the clinical target for plasma urate of <0.36 mmol/L in the majority of patients [2-4].
1. To explore factors that predict allopurinol response.
2. To determine the probability of achieving a plasma urate of <0.36mmol/L under the current renal dosing guideline
3. To determine a dosing regimen that achieves the plasma urate of 75% of simulates.
Results: A total of 1135 oxypurinol and 1178 urate plasma concentrations from 152 patients were available for analysis. A one compartment PK model with first order absorption and elimination was the best fit to the oxypurinol data. A simple direct effects (Emax) model provided an adequate description of the steady-state plasma urate data. A turnover model for urate did not provide a better description and was unstable. Renal function (CL), diuretic use (CL, Emax, baseline urate), and body size (CL, V) were found to be significant covariates. Under the maximum allopurinol doses currently recommended for renally impaired patients, the probability of achieving plasma urate concentrations 30-50, >50-70, >70-90, >90-110, >110 mL/min respectively. Average daily doses to achieve the urate target in >75% of simulates were remarkably consistent (350-400mg) at these CLcr values. Diuretic use and increased body size were found to be primary determinants of maintenance dose requirements.
Discussion: A population PKPD model for allopurinol was developed. Simulations from the model support the contention that CLcr-based dosing for allopurinol will result in suboptimal treatment. The allopurinol doses required to achieve recommended urate concentrations were dependant on diuretic use and body size and were substantially higher than current dosing guidelines.
1. Hande KR et al. (1984) Am J Med 31:667-673
2. Dalbeth N et al. (2006) J Rheumatol 33:1646-1650.
3. Vazquez-Mellado J et al. (2001) Ann Rheum Dis 60:981-983.
4. Stamp LK et al. (2000) Aust NZ J Med 30:567-572.
5. Wright DFB et al. (2013) Eur J Clin Pharmacol 69: 1411-1421