Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout
Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout
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DOI：
10.1002/art.22403
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发表时间：
2007-02-01
影响因子：
--
通讯作者：
Hershfield, Michael S.
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文献类型：
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作者：
Sundy, John S.;Ganson, Nancy J.;Hershfield, Michael S.
客观的。评估静脉内（IV）聚乙二醇化重组哺乳动物尿酸氧化酶（PEG-尿酸酶）治疗严重痛风的功效、免疫原性和耐受性。方法。在一项 I 期临床试验中，24 名患者（6 组，每组 4 名患者）单次输注 PEG-尿酸酶（剂量范围为 0.5 mg 至 12 mg）。给药后 21 天监测血浆尿酸酶活性 (pUox)、血浆尿酸盐浓度 (pUAc) 和尿中尿酸与肌酐比 (UAc:Cr)。不良事件和 IgG 抗体对 PEG-尿酸酶的反应进行了 35 天的随访。结果。所有患者均完成了试验。最大pUox与PEG-尿酸酶的IV剂量呈线性相关，曲线下面积(AUC)值线性增加(直至剂量为8mg)，pUox半衰期为6.4-13.8天。服用 4-12 mg 剂量后，pUAc 在 24-72 小时内从平均+/- SD 值 11.1 +/- 0.6 mg/dl 降至 1.0 +/- 0.5 mg/dl； PUAc 的 AUC 值相当于输注后 21 天将 PUAc 维持在 1.2-4.7 mg/dl。尿液中的 UAc:Cr 比率与 pUAc 平行下降。 9 名患者出现了针对 PEG-尿酸酶的 IgG 抗体，主要是 IgG2，并且对 PEG 具有特异性，这些患者的酶清除速度更快，但没有过敏反应。所有不良事件均为轻度至中度，其中痛风发作最为常见。结论。 IV PEG-尿酸酶的生物利用度、功效和耐受性高于先前皮下注射 PEG-尿酸酶的 I 期试验中观察到的生物利用度、功效和耐受性。每 2-4 周输注 4-12 mg PEG-尿酸酶可将 pUAc 维持在远低于 6 mg/dl 的治疗目标，并大大减少肾脏尿酸排泄。这种治疗可以有效地消耗慢性痛风或痛风石性痛风患者组织中扩大的尿酸盐储存。
Objective. To evaluate the efficacy, immunogenicity, and tolerability of intravenous (IV) PEGylated recombinant mammalian urate oxidase (PEG-uricase) for the treatment of severe gout.Methods. Single infusions of PEG-uricase (at doses ranging from 0.5 mg to 12 mg) were administered to 24 patients (6 cohorts of 4 patients each) in a phase I clinical trial. Plasma uricase activity (pUox), the plasma urate concentration (pUAc), and the uric acid-to-creatinine ratio (UAc:Cr) in urine were monitored for 21 days after dosing. Adverse events and the IgG antibody response to PEG-uricase were followed up for 35 days.Results. All patients completed the trial. Maximum pUox was linearly related to the IV dose of PEG-uricase, the area under the curve (AUC) value increased linearly (up to a dose of 8 mg), and the pUox half-life was 6.4-13.8 days. After doses of 4-12 mg, the pUAc fell within 24-72 hours, from a mean +/- SD value of 11.1 +/- 0.6 mg/dl to 1.0 +/- 0.5 mg/dl; the AUC value for the pUAc was equivalent to maintaining the pUAc at 1.2-4.7 mg/dl for 21 days postinfusion. The UAc:Cr ratio in urine fell in parallel with the pUAc. IgG antibodies to PEG-uricase, mostly IgG2 and specific for PEG, developed in 9 patients, who had more rapid enzyme clearance but no allergic reactions. All adverse events were mild to moderate, with gout flares being most common.Conclusion. The bioavailability, efficacy, and tolerability of IV PEG-uricase were greater than the bioavailability, efficacy, and tolerability observed in a previous phase I trial of subcutaneous PEG-uricase. Infusing 4-12 mg of PEG-uricase every 2-4 weeks should maintain the pUAc well below the therapeutic target of 6 mg/dl and greatly reduce renal uric acid excretion. This treatment could be effective in depleting expanded tissue urate stores in patients with chronic or tophaceous gout.