title: Disposition of Basal Insulin Peglispro Compared with 20-kDa Polyethylene Glycol in Rats Following a Single Intravenous or Subcutaneous Dose.
abstract: Basal insulin peglispro (BIL) comprises insulin lispro covalently bound to a 20-kDa polyethylene glycol (PEG) at lysine B28. The biologic fate of BIL and unconjugated PEG were examined in rats given a single 0.5-mg/kg i.v. or 2-mg/kg s.c. dose of BIL with (14)C label in 20-kDa PEG or (125)I label in lispro. Unconjugated (14)C-labeled 20-kDa PEG was dosed at 10 mg/kg i.v. or s.c. Blood, urine, and feces were collected up to 336 hours after dosing. Radioactivity was measured by scintillation spectrometry, and BIL was quantitated by enzyme-linked immunosorbent assay. Area under the curve and half-life for immunoreactive BIL were lower than those for both (14)C and (125)I after subcutaneous and intravenous administration. The half-lives of (14)C after BIL and PEG dosing were similar. The clearance of immunoreactive BIL was 2.4-fold faster than that of (14)C and 1.6-fold faster than (125)I. After a subcutaneous dose of BIL, immunoreactive BIL accounted for 31% of the circulating (125)I and 16% of the circulating (14)C, indicating extensive catabolism of BIL. Subcutaneous bioavailability of BIL was 23%-29%; bioavailability for unconjugated PEG was 78%. For unconjugated PEG, most of the (14)C dose was recovered in urine. For BIL, ≥86% of (125)I was eliminated in urine and (14)C was eliminated about equally in urine and feces. The major (14)C-labeled catabolism product of BIL in urine was 20-kDa PEG with lysine attached. The attachment of 20-kDa PEG to lispro in BIL led to a different elimination pathway for PEG compared with unconjugated 20-kDa PEG.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana knadler_mary_pat@lilly.com.
authors.forename: Mary Pat
authors.initials: MP
authors.lastname: Knadler
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Bernice B
authors.initials: BB
authors.lastname: Ellis
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Brown-Augsburger
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Murphy
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Martin
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Wroblewski
mesh_terms: D000818:Animals; D001682:Biological Availability; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007328:Insulin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: D007328:Insulin; C039441:insulin, polyethylene glycol(B1)-; D011092:Polyethylene Glycols