Millennium Pharmaceuticals, Inc., Clinical Pharmacology, 35 Landsdowne Street, Cambridge, MA 02139, USA.
Eur J Clin Pharmacol. 2012 Oct;68(10):1347-55. doi: 10.1007/s00228-012-1262-1. Epub 2012 Mar 30.
This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), safety/tolerability, and cardiac safety of liposomal muramyl tripeptide phosphatidyl-ethanolamine [mifamurtide (L-MTP-PE)] in healthy adults.
L-MTP-PE 4 mg was administered intravenously over 30 min. Study participants were monitored from 24 h preinfusion until 72 h postinfusion. Blood samples were drawn over 0-72 h postdose to determine serum MTP-PE, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) concentrations. Electrocardiograpic (ECG) data were collected via continuous Holter monitoring beginning 24 h predose through 24 h postdose. Changes from time-matched pretreatment baseline QTc and associated two-sided 90 % confidence intervals were calculated.
Twenty-one participants received L-MTP-PE. Total serum MTP-PE declined rapidly with a terminal half-life of 2.05 ± 0.40 h. PK variability was low, with <30 % coefficient of variation in systemic exposure. Serum concentrations of IL-6, TNF-α, and CRP increased following L-MTP-PE infusion. Maximum observed increases in IL-6 and TNF-α occurred at 4 and 2 h, respectively, returning toward baseline by 8 h postdose. L-MTP-PE was generally well tolerated, with no adverse events greater than grade 3. Headache, chills, tachycardia, nausea, and pyrexia were the most frequent adverse events. L-MTP-PE infusion resulted in an increased heart rate without readily apparent QTc prolongation.
MTP-PE PK following L-MTP-PE administration were characterized by a short serum half-life and low variability. Increases in IL-6, TNF-α, and CRP and the safety profile were consistent with the immunomodulatory mechanism of action. No clinically significant effect of L-MTP-PE on cardiovascular repolarization was observed based on analysis of ECG QTc intervals.
本研究评估了脂质体胞壁酰二肽磷脂酰乙醇胺[米夫单抗（L-MTP-PE）]在健康成年人中的药代动力学（PK）、药效学（PD）、安全性/耐受性和心脏安全性。
L-MTP-PE 4mg 静脉输注 30 分钟。研究参与者从给药前 24 小时开始监测，直至给药后 72 小时。给药后 0-72 小时内抽取血样，以确定血清 MTP-PE、白细胞介素（IL）-6、肿瘤坏死因子（TNF）-α 和 C 反应蛋白（CRP）浓度。通过连续 Holter 监测从给药前 24 小时开始收集心电图（ECG）数据，直至给药后 24 小时。计算 QTc 与时间匹配的预处理基线的变化，并计算双侧 90%置信区间。
21 名参与者接受了 L-MTP-PE 治疗。总血清 MTP-PE 迅速下降，终末半衰期为 2.05±0.40 小时。PK 变异性低，全身暴露的变异系数<30%。L-MTP-PE 输注后血清 IL-6、TNF-α 和 CRP 浓度增加。IL-6 和 TNF-α 的最大观察到的增加分别发生在 4 小时和 2 小时，给药后 8 小时恢复到基线水平。L-MTP-PE 一般耐受性良好，无大于 3 级的不良事件。头痛、寒战、心动过速、恶心和发热是最常见的不良事件。L-MTP-PE 输注导致心率增加，而无明显的 QTc 延长。
L-MTP-PE 给药后 MTP-PE 的 PK 特征为血清半衰期短且变异性低。IL-6、TNF-α 和 CRP 的增加以及安全性概况与免疫调节作用机制一致。根据 ECG QTc 间隔分析，未观察到 L-MTP-PE 对心血管复极化有临床意义的影响。
