- To develop a population PKPD model for plasma allopurinol, oxypurinol and serum urate
- To investigate the best regimen for dosing allopurinol in patients with renal impairment
- The data were sourced from four studies (one unpublished).1-3 The population analysis was conducted using NONMEM® v.7.2. Covariates analysed included creatinine clearance (as predicted from the Cockcroft-Gault equation), body weight (total and lean), diuretic use, and aldehyde oxide (AOX1) and MOCOS genotypes.
- The final PKPD model was coded in MATLAB (2011a). Mean urate response was simulated deterministically for 30 days of allopurinol therapy at six dose levels (100, 150, 200, 250, 300 and 400mg) and at six values of CLCR (20, 30, 40, 60, 100 and 140 mL/min). Baseline urate concentration was fixed at 0.486 mmol/L. The ability of each regimen to achieve the target serum urate of <0.36 mmol/L was compared to current dosing guidelines.4
- A total of 680 allopurinol and oxypurinol observations from 88 patients and 556 urate concentrations from 76 patients were available for analysis. The allopurinol (parent drug) data fit a 2 compartment model and oxypurinol a 1 compartment model, both with a combined RUV error model and covariance between for CL and V. The serum urate was described by a turnover model with inhibition of urate formation. Covariates which explained between subject differences were renal function on oxypurinol and urate CL, frusemide use on oxypurinol CL and fat-free mass on allopurinol and oxypurinol CL and V.
- Target serum urate concentrations of < 0.36 mmol/L were achieved with a simulated dose of Xmg when CLCR was 140 mL/min, Xmg at a CLCR of 100 mL/min, Xmg at a CLCR of 60 mL/min, Xmg at a CLCR of 40 mL/min, Xmg at a CLCR of 40 mL/min, and , Xmg at a CLCR of 20 mL/min. Doses to achieve this target were consistently greater than those recommended by current renal dosing guidelines.4
A PKPD model for allopurinol in gout patients was developed. Simulations from the model support the contention that CRCL-based dosing will result in suboptimal treatment response in patients with impaired renal function. On average, the allopurinol doses required to achieve a target serum urate of 0.36mmol/L were consistently greater than those recommended by current renal dosing guidelines.
1. Stamp LK, Barclay ML, O’Donnell JL, Zhang M, Drake J, Frampton C, et al. Relationship Between Serum Urate and Plasma Oxypurinol in the Management of Gout. Clin Pharmacol Ther. 2011:90:392-8
2. Appelbaum SJ, Mayersohn M, Dorr RT, Perrier D. Allopurinol kinetics and bioavailability. Cancer Chemother Pharmacol. 1982:8:93-98
3. Breithaupt H, Tittel M. Kinetics of allopurinol after single intravenous and oral doses. Eur J Clin Pharmacol. 1982:22:77-84
4. Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity: Description and guidelines for prevention in patients with renal insufficiency. Am J Med. 1984:31:667-673