title: Addition of 20-kDa PEG to Insulin Lispro Alters Absorption and Decreases Clearance in Animals.
abstract: Determine the pharmacokinetics of insulin peglispro (BIL) in 5/6-nephrectomized rats and study the absorption in lymph duct cannulated (LDC) sheep.
  
  
  
  BIL is insulin lispro modified with 20-kDa linear PEG at lysine B28 increasing the hydrodynamic size to 4-fold larger than insulin lispro. Pharmacokinetics of BIL and insulin lispro after IV administration were compared in 5/6-nephrectomized and sham rats. BIL was administered IV or SC into the interdigital space of the hind leg, and peripheral lymph and/or serum samples were collected from both LDC and non-LDC sheep to determine pharmacokinetics and absorption route of BIL.
  
  
  
  The clearance of BIL was similar in 5/6-nephrectomized and sham rats, while the clearance of insulin lispro was 3.3-fold slower in 5/6-nephrectomized rats than in the sham rats. In non-LDC sheep, the terminal half-life after SC was about twice as long vs IV suggesting flip-flop pharmacokinetics. In LDC sheep, bioavailability decreased to <2%; most of the dose was absorbed via the lymphatic system, with 88% ± 19% of the dose collected in the lymph after SC administration.
  
  
  
  This work demonstrates that increasing the hydrodynamic size of insulin lispro through PEGylation can impact both absorption and clearance to prolong drug action.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, USA. knadler_mary_pat@lilly.com.
authors.forename: Mary Pat
authors.identifier: 0000-0001-7133-1331
authors.initials: MP
authors.lastname: Knadler
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
authors.forename: Tri-Hung
authors.initials: TH
authors.lastname: Nguyen
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Campanale
authors.affiliation: Department of Physiology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Victoria, 3800, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: De Veer
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Beals
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, USA.
authors.forename: Shun
authors.initials: S
authors.lastname: Li
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Hansen
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Siesky
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285, USA.
authors.forename: M Dodson
authors.initials: MD
authors.lastname: Michael
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.|ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Christopher J H
authors.initials: CJ
authors.lastname: Porter
mesh_terms: D000818:Animals; D001682:Biological Availability; D016503:Drug Delivery Systems; D065546:Drug Liberation; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D061268:Insulin Lispro / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D007700:Kinetics; D008196:Lymph / Q000187:drug effects*; D008297:Male; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000737:chemistry*; D017207:Rats, Sprague-Dawley; D012756:Sheep
chemical_list: D007004:Hypoglycemic Agents; D061268:Insulin Lispro; D011092:Polyethylene Glycols
keywords: insulin peglispro; lymphatic absorption; sheep model