title: Pharmacokinetics and pharmacodynamics of liposomal mifamurtide in adult volunteers with mild or moderate hepatic impairment.
abstract: OBJECTIVE
  To evaluate the pharmacokinetics and pharmacodynamics after a single dose of liposomal mifamurtide (liposomal muramyl tripeptide phospatidyl ethanolamine; MEPACT(®)) in adult subjects with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment in comparison with age-, weight- and sex-matched healthy subjects with normal hepatic function.
  
  
  METHODS
  Subjects received a 4 mg dose of liposomal mifamurtide via 1 h intravenous infusion. Blood samples were collected over 72 h for pharmacokinetic and pharmacodynamic assessments (changes in serum interleukin-6, tumour necrosis factor-α and C-reactive protein).
  
  
  RESULTS
  Thirty-seven subjects were enrolled: nine with mild hepatic impairment, eight with moderate hepatic impairment and 20 matched healthy subjects. Geometric least-square mean ratios of total mifamurtide AUCinf for the mild hepatic impairment and moderate hepatic impairment groups vs. matched healthy subjects were 105% (90% confidence interval, 83.6-132%) and 119% (90% confidence interval, 94.1-151%), respectively, which are below the protocol-specified threshold (150%) to require development of dose-modification recommendations. Pharmacodynamic parameters for changes in serum interleukin-6 and tumour necrosis factor-α concentrations were generally similar across hepatic function groups. Mifamurtide-induced increases in serum C-reactive protein were attenuated in the moderate hepatic impairment group, consistent with the liver being the major organ of C-reactive protein synthesis. No grade ≥3 adverse events were seen in subjects administered mifamurtide (4 mg).
  
  
  CONCLUSIONS
  These results support the conclusion that mild or moderate hepatic impairment does not produce clinically meaningful effects on the clinical pharmacokinetics or pharmacodynamics of mifamurtide; no dose modifications are needed in these special patient populations based on clinical pharmacological considerations.
authors.affiliation: Clinical Pharmacology, Takeda Pharmaceuticals International Company, Cambridge, MA, USA.
authors.forename: Karthik
authors.initials: K
authors.lastname: Venkatakrishnan
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Dennis
authors.initials: D
authors.lastname: Noe
authors.forename: Jaime
authors.initials: J
authors.lastname: Mertz
authors.forename: Michael
authors.initials: M
authors.lastname: Bargfrede
authors.forename: Thomas
authors.initials: T
authors.lastname: Marbury
authors.forename: Kambiz
authors.initials: K
authors.lastname: Farbakhsh
authors.forename: Cristina
authors.initials: C
authors.lastname: Oliva
authors.forename: Ashley
authors.initials: A
authors.lastname: Milton
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000493:pharmacokinetics*; D000328:Adult; D019540:Area Under Curve; D002097:C-Reactive Protein / Q000032:analysis; D005260:Female; D048550:Hepatic Insufficiency / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D010714:Phosphatidylethanolamines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000276:Adjuvants, Immunologic; D015850:Interleukin-6; D008081:Liposomes; D010714:Phosphatidylethanolamines; D014409:Tumor Necrosis Factor-alpha; C037144:mifamurtide; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D002097:C-Reactive Protein
keywords: MEPACT®; hepatic impairment; liposomes; mifamurtide; pharmacodynamics; pharmacokinetics