title: A pharmacokinetic, pharmacodynamic, and electrocardiographic study of liposomal mifamurtide (L-MTP-PE) in healthy adult volunteers.
abstract: OBJECTIVE
  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.
authors.affiliation: Millennium Pharmaceuticals, Inc., Clinical Pharmacology, 35 Landsdowne Street, Cambridge, MA 02139, USA. karthik.venkatakrishnan@mpi.com
authors.forename: Karthik
authors.initials: K
authors.lastname: Venkatakrishnan
authors.forename: William G
authors.initials: WG
authors.lastname: Kramer
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Synold
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Goodman
authors.forename: Evin
authors.initials: E
authors.lastname: Sides
authors.forename: Cristina
authors.initials: C
authors.lastname: Oliva
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000328:Adult; D019540:Area Under Curve; D002097:C-Reactive Protein / Q000378:metabolism; D004562:Electrocardiography / Q000379:methods; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008081:Liposomes / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D010714:Phosphatidylethanolamines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011446:Prospective Studies; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism; D055815:Young Adult
chemical_list: D015850:Interleukin-6; D008081:Liposomes; D010714:Phosphatidylethanolamines; D014409:Tumor Necrosis Factor-alpha; C037144:mifamurtide; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D002097:C-Reactive Protein