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.