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 ¹⁴C label in 20-kDa PEG or ¹²⁵I label in lispro. Unconjugated ¹⁴C-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 ¹⁴C and ¹²⁵I after subcutaneous and intravenous administration. The half-lives of ¹⁴C after BIL and PEG dosing were similar. The clearance of immunoreactive BIL was 2.4-fold faster than that of ¹⁴C and 1.6-fold faster than ¹²⁵I. After a subcutaneous dose of BIL, immunoreactive BIL accounted for 31% of the circulating ¹²⁵I and 16% of the circulating ¹⁴C, indicating extensive catabolism of BIL. Subcutaneous bioavailability of BIL was 23%–29%; bioavailability for unconjugated PEG was 78%. For unconjugated PEG, most of the ¹⁴C dose was recovered in urine. For BIL, ≥86% of ¹²⁵I was eliminated in urine and ¹⁴C was eliminated about equally in urine and feces. The major ¹⁴C-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.