Background: Allopurinol, a pro-drug of oxypurinol, is the most common medicine used for prophylactic management of gout. The active metabolite of allopurinol, oxypurinol, is responsible for the urate lowering effect of allopurinol and is primarily renally excreted. Treatment response to allopurinol is variable in people with gout supporting the need for more information about factors which influence oxypurinol pharmacokinetics and pharmacodynamics to inform optimal dose regimens and allopurinol dose individualisation.
Aim: (1) To develop and evaluate a population pharmacokinetic for oxypurinol in people receiving allopurinol for gout prophylaxis and (2) to explore patient factors which contribute to inter-individual patient variability in oxypurinol pharmacokinetics.
Methods: This was an observational clinical study in patients at St Vincent’s Hospital (Darlinghurst, Sydney) receiving allopurinol for gout. Blood samples were taken for measurement of plasma oxypurinol, uric acid and creatinine concentrations. A detailed medication and clinical history was collected. A population pharmacokinetic modelling approach using NONMEM VI with FOCEI was undertaken. The influence of between occasion variability (BOV), patient characteristics and concomitant medication(s) were screened for significance and included in a stepwise manner. The model selection was based on the generated objective function (OFV) value and diagnostic plots.
Results: 923 oxypurinol concentrations were obtained from 132 in-patients receiving allopurinol. The final base model was a one compartment model with first-order absorption with BSV on CL and V and a combined residual model. The estimated population apparent clearance of oxypurinol of 1.46 L/h (inter-subject variability 43%) is slightly higher than that reported for healthy volunteers (1.3 L/h) (Day et al., 2007). The inclusion of BOV on the apparent clearance of oxypurinol significantly improved the model, reducing the OFV by 73 and provided an estimate of BOVCL of 27%. Those patients taking diuretics had a 26% reduction in the clearance of oxypurinol.
Conclusions: A population pharmacokinetic model for oxypurinol has been developed. The concomitant used of diuretics, primarily frusemide, was found to decrease the apparent clearance of oxypurinol in patients with gout. These data will be used to review allopurinol dose regimens and strategies to improve gout management.
References:
- Day RO, Graham GG, Hicks M, McLachlan AJ, Stocker SL, Williams KM (2007). Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol. Clin Pharmacokinet46(8):623-644.