Daniel F.B. Wright (1), Stephen B. Duffull (1), Tony R. Merriman (2), Murray L. Barclay (3), Lisa K. Stamp (3)
(1) School of Pharmacy, (2) Department of Biochemistry, (3) Department of Medicine, University of Otago, Dunedin (1,2) and Christchurch (3), New Zealand.
Objectives:
- To explore factors that predict allopurinol response in patients with gout.
- To determine the probability of achieving the recommended plasma urate of ≤0.36mmol/L under the current renal dosing guideline [1]
- To predict the maintenance doses required to achieve the target plasma urate.
Methods: The data were sourced from five studies (summarised in [2]). A population analysis was conducted using NONMEM® v.7.2. Covariates analysed included renal function, body size, sex, race, concomitant drugs, and renal transporter genotype. The final PKPD model was implemented in MATLAB (2014a). Stochastic simulations were performed under two scenarios; 1) using doses recommended by the current renal dosing guideline, and 2) using daily doses sufficient to achieve target plasma urate concentrations in >75% of simulates.
Results: A total of 1135 oxypurinol and 1178 urate plasma concentrations from 134 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 ≤0.36 mmol/L for a 70kg patient not taking diuretics was 12%, 29%, 44%, 56% , and 64% for CLcr values of 20, 40, 60, 80, and 100 mL/min respectively. Diuretic use and increased body size were found to be primary determinants of maintenance dose requirements. Dose requirements were found to increase approximately 2-fold over a 3-fold range of weights and were 1.25-2 times higher in those taking diuretics. Renal function had only a relatively minor impact on allopurinol dosing. The model performed well when evaluated against external urate data.
Conclusions: 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 PKPD model provides a means of predicting allopurinol maintenance dose requirements for individual patients.
References:
[1] Hande KR et al. (1984) Am J Med 31:667-673
[2] Wright DFB et al. (2013) Eur J Clin Pharmacol 69: 1411-1421
Reference: PAGE 24 () Abstr 3338 [www.page-meeting.org/?abstract=3338]
Poster: Drug/Disease modeling - Other topics