阿达木单抗治疗局灶节段性肾小球硬化症（FSGS）的 1 期临床试验：II. FONT（治疗难治性 FSGS 的新型疗法）研究组报告。
Phase 1 trial of adalimumab in Focal Segmental Glomerulosclerosis (FSGS): II. Report of the FONT (Novel Therapies for Resistant FSGS) study group.
机构信息
UNC Kidney Center and Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
出版信息
Am J Kidney Dis. 2010 Jan;55(1):50-60. doi: 10.1053/j.ajkd.2009.08.019. Epub 2009 Nov 22.
BACKGROUND
Patients with primary focal segmental glomerulosclerosis (FSGS) resistant to current treatment regimens are at high risk of progression to end-stage kidney disease. Antifibrotic agents, such as tumor necrosis factor alpha antagonists, are a promising strategy to slow or halt the decline in renal function, based on preclinical and clinical data.
STUDY DESIGN
Phase 1 clinical trial to assess the pharmacokinetics, tolerability, and safety of adalimumab, a human monoclonal antibody to tumor necrosis factor alpha.
SETTING & PARTICIPANTS: 10 patients (4 male and 6 female) aged 16.8 +/- 9.0 years with an estimated glomerular filtration rate of 105 +/- 50 mL/min/1.73 m(2) were studied.
INTERVENTION
Adalimumab, 24 mg/m(2), every 14 days for 16 weeks (total, 9 doses).
OUTCOMES
Pharmacokinetic assessment, tolerability, and safety.
MEASUREMENTS
Estimated glomerular filtration rate, proteinuria, and pharmacokinetic assessment after initial dosing and steady state.
RESULTS
Pharmacokinetic evaluation indicated that the area under the curve was decreased by 54% (P < 0.001) and clearance was increased by 160% (P < 0.01) in patients with resistant FSGS compared with healthy controls and patients with rheumatoid arthritis. Adalimumab was well tolerated with no serious adverse events or infectious complications attributable to the drug. Proteinuria decreased by > or = 50% in 4 of 10 treated patients.
LIMITATIONS
Insufficient power to assess the safety or efficacy of adalimumab therapy for patients with resistant FSGS.
CONCLUSIONS
Pharmacokinetic assessment showed increased clearance of adalimumab in patients with resistant primary FSGS and validated the need to evaluate the disposition of novel therapies for this disease to define appropriate dosing regimens. The study provides a rationale to evaluate the efficacy of adalimumab as an antifibrotic agent for resistant FSGS in phase 2/3 clinical trials.
背景
目前治疗方案无效的原发性局灶节段性肾小球硬化症（FSGS）患者，进展为终末期肾病的风险很高。基于临床前和临床数据，抗纤维化药物，如肿瘤坏死因子-α拮抗剂，是一种减缓或阻止肾功能下降的有前途的策略。
研究设计
评估肿瘤坏死因子-α人单克隆抗体阿达木单抗的药代动力学、耐受性和安全性的 I 期临床试验。
设置和参与者
10 名患者（4 名男性和 6 名女性），年龄 16.8 ± 9.0 岁，估算肾小球滤过率为 105 ± 50 mL/min/1.73 m(2)。
干预措施
阿达木单抗，24mg/m(2)，每 14 天一次，共 16 周（共 9 剂）。
结果
药代动力学评估、耐受性和安全性。
测量
初剂量和稳态后估算肾小球滤过率、蛋白尿和药代动力学评估。
结果
药代动力学评估表明，与健康对照者和类风湿关节炎患者相比，耐药性 FSGS 患者的曲线下面积降低了 54%（P < 0.001），清除率增加了 160%（P < 0.01）。阿达木单抗耐受性良好，无药物相关的严重不良事件或感染并发症。10 名治疗患者中有 4 名蛋白尿减少≥50%。
局限性
评估阿达木单抗治疗耐药性 FSGS 患者的安全性或疗效的效力不足。
结论
药代动力学评估显示，耐药性原发性 FSGS 患者阿达木单抗清除率增加，验证了需要评估新型疗法在该疾病中的处置情况，以确定适当的给药方案。该研究为评估阿达木单抗作为抗纤维化药物治疗耐药性 FSGS 的疗效提供了依据，将在 II/III 期临床试验中进行。
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