title: Pharmacokinetics and pharmacodynamics of liposomal mifamurtide in adult volunteers with mild or moderate renal impairment.
abstract: OBJECTIVE
  To evaluate the pharmacokinetics and pharmacodynamics following a single dose of liposomal mifamurtide (L-MTP-PE, MEPACT(®)) in adult subjects with mild (calculated creatinine clearance [CLcr ] of 50-80 ml min(-1)) or moderate (CLcr 30-50 ml min(-1)) renal impairment in comparison with age-, weight- and gender-matched healthy subjects with normal renal function (CLcr >80 ml min(-1)).
  
  
  METHODS
  Subjects received a 4 mg dose of liposomal mifamurtide via 1 h intravenous infusion. Blood samples were collected over 72 h for analysis of plasma pharmacokinetics of total and non-liposome-associated (free) mifamurtide and assessment of pharmacodynamics (changes in serum interleukin-6 [IL-6], tumour necrosis factor-α [TNF-α], C-reactive protein [CRP]).
  
  
  RESULTS
  Thirty-three subjects were enrolled: nine with mild renal impairment, eight with moderate renal impairment and 16 healthy subjects. Geometric mean (%CV) AUCinf for total mifamurtide was 89.5 (58.1), 94.8 (27.8), 85.1 (29.0), 95.4 (18.1) nM h in the mild renal impairment, mild-matched healthy subject, moderate renal impairment and moderate-matched healthy subject groups, respectively. Mifamurtide clearance was not correlated with CLcr, estimated glomerular filtration rate or iohexol clearance (all r(2) < 0.01). AUCinf of free mifamurtide was similar across the renal function groups. There were no readily apparent differences in serum pharmacodynamic effect parameters (baseline-adjusted AUEClast for IL-6 and TNF-α and Emax for CRP) between the renal function groups. No subjects reported grade ≥3 or serious adverse events.
  
  
  CONCLUSIONS
  Mild or moderate renal impairment does not alter the clinical pharmacokinetics or pharmacodynamics of mifamurtide. No dose modifications appear necessary for these patients based on clinical pharmacologic 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 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000276:Adjuvants, Immunologic / Q000493:pharmacokinetics*; D000328:Adult; D000368:Aged; D002097:C-Reactive Protein / Q000032:analysis; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D010714:Phosphatidylethanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051437:Renal Insufficiency / Q000378:metabolism*; 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®; liposomes; mifamurtide; pharmacodynamics; pharmacokinetics; renal impairment