Mifamurtide in metastatic and recurrent osteosarcoma: a patient access study with pharmacokinetic, pharmacodynamic, and safety assessments.
Mifamurtide in metastatic and recurrent osteosarcoma: a patient access study with pharmacokinetic, pharmacodynamic, and safety assessments.
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DOI：
10.1002/pbc.24686
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发表时间：
2014-02
影响因子：
3.2
通讯作者：
Chou A
中科院分区：
文献类型：
--
作者：
Anderson PM;Meyers P;Kleinerman E;Venkatakrishnan K;Hughes DP;Herzog C;Huh W;Sutphin R;Vyas YM;Shen V;Warwick A;Yeager N;Oliva C;Wang B;Liu Y;Chou A
该非随机、患者访问方案评估了脂质体胞壁酰三肽磷脂酰乙醇胺（L-MTP-PE; mifamurtide）治疗高危、复发和/或转移性骨肉瘤患者的安全性和疗效结局。患者接受mifamurtide 2 mg/m2静脉给药，每周2次×12周，然后每周1次×24周，伴或不伴化疗。收集血清浓度-时间曲线。给药后24小时内的不良事件被归类为输注相关不良事件（IRAE）;评估其他AE和总生存期（OS）。该研究于2008年1月开始治疗;最后一名患者于2012年10月完成治疗。入组了205例患者;中位年龄为16.5岁，143/204（72%）例患者患有活动性疾病。米法莫肽血清浓度在输注后前30分钟内迅速下降，然后在给药后2-6小时以对数线性方式下降; t1/2为2小时。年龄与BSA标准化清除率、半衰期或药效学效应之间没有明显的关系，支持2 mg/m2 mifamurtide在整个年龄范围内的剂量。患者在7，122次mifamurtide输注后报告了3，415例IRAE。这些很少为3级或4级，最常见的包括寒战+发热或头痛+疲劳症状群。1年和2年OS分别为70.6%和41.4%。在诊断后9个月内发生初始转移性疾病或进展的患者（N=40）的2年OS（38.8%）与整个队列（41.4%）相似，米伐莫肽具有可管理的安全性特征;本患者入组研究中米伐莫肽的PK/PD与既往研究一致。2年OS为41.4%。需要进行随机临床试验，以明确确定对患者结局的影响。
This non-randomized, patient-access protocol, assessed both safety and efficacy outcomes following liposomal muramyl –tripeptide-phosphatidylethanolamine (L-MTP-PE; mifamurtide) in patients with high-risk, recurrent and/or metastatic osteosarcoma. Patients received mifamurtide 2 mg/m2 intravenously twice-weekly ×12 weeks, then weekly ×24 weeks with and without chemotherapy. Serum concentration-time profiles were collected. Adverse events within 24 hours of drug administration were classified as infusion-related adverse events (IRAE); other AEs and overall survival (OS) were assessed. The study began therapy in January 2008; the last patient completed therapy in October 2012. 205 patients were enrolled; median age was 16.5 years and 143/204 (72%) had active disease. Mifamurtide serum concentrations declined rapidly in the first 30 minutes post-infusion, then in a loglinear manner 2–6 hours post-dose; t1/2 was 2 hours. There were no readily apparent relationships between age and BSA-normalized clearance, half-life, or pharmacodynamic effects, supporting the dose of 2 mg/m2 mifamurtide across the age range. Patients reported 3,415 IRAE after 7,122 mifamurtide infusions. These were very rarely grade 3 or 4 and most commonly included chills+fever or headache+fatigue symptom clusters. One and two year OS was 70.6% and 41.4%. Patients with initial metastatic disease or progression approximated by within 9 months of diagnosis (N=40) had similar 2-year OS (38.8%) as the entire cohort (41.4%) Mifamurtide had a manageable safety profile; PK/PD of mifamurtide in this patient access study was consistent with prior studies. Two-year OS was 41.4%. A randomized clinical trial would be required to definitively determine impact on patient outcomes.