title: Single-dose pharmacokinetics and glucodynamics of the novel, long-acting basal insulin LY2605541 in healthy subjects.
abstract: LY2605541 is a novel basal insulin analog with a prolonged duration of action. Two Phase I studies assessed LY2605541 pharmacokinetics (PK), glucodynamics (GD), and tolerability in healthy subjects. In Study 1, 33 subjects received single subcutaneous (SC) doses of LY2605541 (0.01-2.22 U/kg) and insulin glargine (0.5-0.8 U/kg) followed by euglycemic clamp for up to 24-36 hours. In Study 2, absolute bioavailability of SC LY2605541 was assessed in 8 subjects by comparing dose normalized area under concentration versus time curve of SC against IV administration. Time-to-maximum plasma concentration (medians) and geometric means for half-life (t½ ) and apparent clearance, respectively, ranged from 18.0 to 42.0 hours, 24.4-45.5 hours, and 1.8-2.8 L/h for SC LY2605541, versus 10.0-12.0 hours, 12.2-14.9 hours, and 51.4-65.2 L/h for SC insulin glargine. LY2605541 glucose infusion rate (GIR) profiles were sustained for ≥36 hours versus glargine GIR profiles, which waned at 24 hours. After IV administration, LY2605541's geometric mean t½ was 2.3 hours. LY2605541 intra-subject variability (CV%) was <18% for PK and <32% for GD parameters. The most common adverse events were related to study procedures and were mild-moderate in severity. These results established a well-tolerated baseline dose for LY2605541 with a relatively flat PK profile and low intra-subject variability.
authors: Eli Lilly and Company, Indianapolis, IN, USA.
authors: Vikram P
authors: VP
authors: Sinha
authors: Siak Leng
authors: SL
authors: Choi
authors: Danny Kwang Wei
authors: DK
authors: Soon
authors: Kenneth F
authors: KF
authors: Mace
authors: Kwee Poo
authors: KP
authors: Yeo
authors: Shufen T H
authors: ST
authors: Lim
authors: Daniel C
authors: DC
authors: Howey
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult; D001682:Biological Availability; D001786:Blood Glucose / Q000032:analysis; D015331:Cohort Studies; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics; D015309:Glucose Clamp Technique; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D000069036:Insulin Glargine; D061268:Insulin Lispro / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D049528:Insulin, Long-Acting / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D008657:Metabolic Clearance Rate; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D015203:Reproducibility of Results
chemical_list: D001786:Blood Glucose; D015507:Drugs, Investigational; D007004:Hypoglycemic Agents; D000069036:Insulin Glargine; D061268:Insulin Lispro; D049528:Insulin, Long-Acting; C587357:LY2605541; D011092:Polyethylene Glycols
keywords: glucodynamics; long-acting basal insulin; pharmacokinetics