Chronic Toxicology Studies of Basal Insulin Peglispro in Rats and Dogs: A Novel, PEGylated Insulin Lispro Analog with a Prolonged Duration of Action.

Basal insulin peglispro (BIL) consists of insulin lispro with a 20-kDa polyethylene glycol (PEG) moiety covalently attached to lysine B28. Because chronic parenteral administration of PEGylated proteins to animals has sometimes resulted in PEG vacuolation of tissue macrophages, renal tubular cells, and choroid plexus ependymal cells, we investigated whether chronic subcutaneous (sc) injection of BIL in rats (52 weeks) and dogs (39 weeks) was associated with systemic toxicities or other changes, including vacuolation of tissue macrophages, renal tubular cells, and ependymal cells. Rats and dogs received daily sc injections of BIL (rats: 0.

Quantification of Basal Insulin Peglispro and Human Insulin in Adipose Tissue Interstitial Fluid by Open-Flow Microperfusion.

Background: Restoration of the physiologic hepatic-to-peripheral insulin gradient may be achieved by either portal vein administration or altering insulin structure to increase hepatic specificity or restrict peripheral access. Basal insulin peglispro (BIL) is a novel, PEGylated basal insulin with a flat pharmacokinetic and glucodynamic profile and altered hepatic-to-peripheral action gradient. We hypothesized reduced BIL exposure in peripheral tissues explains the latter, and in this study assessed the adipose tissue interstitial fluid (ISF) concentrations of BIL compared with human insulin (HI).

In Vitro and Clinical Evaluations of the Drug-Drug Interaction Potential of a Metabotropic Glutamate 2/3 Receptor Agonist Prodrug with Intestinal Peptide Transporter 1.

Despite peptide transporter 1 (PEPT1) being responsible for the bioavailability for a variety of drugs, there has been little study of its potential involvement in drug-drug interactions. Pomaglumetad methionil, a metabotropic glutamate 2/3 receptor agonist prodrug, utilizes PEPT1 to enhance absorption and bioavailability. In vitro studies were conducted to guide the decision to conduct a clinical drug interaction study and to inform the clinical study design.

Novel hepato-preferential basal insulin peglispro (BIL) does not differentially affect insulin sensitivity compared with insulin glargine in patients with type 1 and type 2 diabetes.

Aims: Basal insulin peglispro (BIL) is a novel PEGylated basal insulin with a flat pharmacokinetic and glucodynamic profile and reduced peripheral effects, which results in a hepato-preferential action. In Phase 3 trials, patients with T1DM treated with BIL had lower prandial insulin requirements, yet improved prandial glucose control, relative to insulin glargine (GL). We hypothesized that this may be because of an enhanced sensitivity to prandial insulin with BIL resulting from lower chronic peripheral insulin action.

Addition of 20-kDa PEG to Insulin Lispro Alters Absorption and Decreases Clearance in Animals.

Purpose: Determine the pharmacokinetics of insulin peglispro (BIL) in 5/6-nephrectomized rats and study the absorption in lymph duct cannulated (LDC) sheep.

Methods: 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.