Wright Daniel Fb, Doogue Matthew P, Barclay Murray L, Chapman Peter T, Cross Nicholas B, Irvine John H, Stamp Lisa K
School of Pharmacy, University of Otago, PO Box 56, Dunedin, 9054, New Zealand.
Department of Medicine, University of Otago, Christchurch, New Zealand.
Eur J Clin Pharmacol. 2017 Jan;73(1):71-78. doi: 10.1007/s00228-016-2133-y. Epub 2016 Sep 28.
The aims of this study were to characterise the population pharmacokinetics of oxypurinol in patients receiving haemodialysis and to compare oxypurinol exposure in dialysis and non-dialysis patients.
Oxypurinol plasma concentrations from 6 gout people receiving haemodialysis and 19 people with gout not receiving dialysis were used to develop a population pharmacokinetic model in NONMEM. Deterministic simulations were used to predict the steady-state area under the oxypurinol plasma concentration time curve over 1 week (AUC).
The pharmacokinetics of oxypurinol were best described by a one-compartment model with a separate parameter for dialytic clearance. Allopurinol 100 mg daily produced an AUC of 279 μmol/L h in dialysis patients, a value 50-75 % lower than the AUC predicted for patients with normal renal function taking 200 to 400 mg daily (427-855 μmol/L h). Dosing pre-dialysis resulted in about a 25-35 % reduction in exposure compared to post-dialysis.
Oxypurinol is efficiently removed by dialysis. The population dialytic and total (non-dialytic) clearance of oxypurinol were found to be 8.23 and 1.23 L/h, standardised to a fat-free mass of 70 kg and creatinine clearance of 6 L/h, respectively. Our results suggest that if the combination of low-dose allopurinol and haemodialysis does not result in sustained urate lowering below treatment targets (serum urate ≤0.36 mmol/L), then allopurinol doses may be increased to optimise oxypurinol exposure.
本研究旨在描述接受血液透析患者中氧嘌呤醇的群体药代动力学特征，并比较透析患者和非透析患者的氧嘌呤醇暴露情况。
使用6例接受血液透析的痛风患者和19例未接受透析的痛风患者的氧嘌呤醇血浆浓度，在NONMEM中建立群体药代动力学模型。采用确定性模拟来预测氧嘌呤醇血浆浓度-时间曲线下1周的稳态面积（AUC）。
氧嘌呤醇的药代动力学最好用具有单独透析清除参数的单室模型来描述。每日100 mg别嘌醇在透析患者中产生的AUC为279 μmol/L·h，该值比肾功能正常且每日服用200至400 mg别嘌醇患者预测的AUC（427 - 855 μmol/L·h）低50 - 75%。与透析后给药相比，透析前给药导致暴露量降低约25 - 35%。
氧嘌呤醇可通过透析有效清除。发现氧嘌呤醇的群体透析清除率和总（非透析）清除率分别为8.23和1.23 L/h，以70 kg无脂肪体重和6 L/h肌酐清除率进行标准化。我们的结果表明，如果低剂量别嘌醇与血液透析联合使用未导致尿酸持续降低至治疗目标以下（血清尿酸≤0.36 mmol/L），则可增加别嘌醇剂量以优化氧嘌呤醇暴露。
