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Eur J Clin Pharmacol ; 68(10): 1347-55, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22460239

ABSTRACT

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Subject(s)
Acetylmuramyl-Alanyl-Isoglutamine/analogs & derivatives , Heart/drug effects , Phosphatidylethanolamines/administration & dosage , Phosphatidylethanolamines/pharmacokinetics , Acetylmuramyl-Alanyl-Isoglutamine/administration & dosage , Acetylmuramyl-Alanyl-Isoglutamine/adverse effects , Acetylmuramyl-Alanyl-Isoglutamine/pharmacokinetics , Adult , Area Under Curve , C-Reactive Protein/metabolism , Electrocardiography/methods , Female , Heart/physiology , Humans , Interleukin-6/blood , Interleukin-6/metabolism , Liposomes/administration & dosage , Male , Middle Aged , Phosphatidylethanolamines/adverse effects , Prospective Studies , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/metabolism , Young Adult
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