Steady-state pharmacokinetics and glucodynamics of the novel, long-acting basal insulin LY2605541 dosed once-daily in patients with type 2 diabetes mellitus

Diabetes Obes Metab. 2014 Apr;16(4):344-50. doi: 10.1111/dom.12222. Epub 2013 Oct 31.

Abstract

Aims: To assess the pharmacokinetics (PK) and glucodynamics (GD) of LY2605541 in patients with type 2 diabetes mellitus.

Methods: This parallel-group, open-label, dose-escalation study examined the PK and GD of basal insulin LY2605541 after single and multiple-dose administration. Fixed doses of LY2605541 (0.33-1.00 U/kg) were given once-daily (QD) for 14 days to insulin-treated patients with type 2 diabetes. A 24-h euglycaemic glucose clamp was conducted on days 1 and 14.

Results: PK steady state was achieved within 7-10 days and the peak-to-trough fluctuation was <2, translating to a nearly 'peakless' glucose infusion rate at steady state and with a duration of action of at least 24 h. Across dose levels t1/2 ranged from 44.7 to 75.5 h (~2-3 days). As steady state was achieved, there were dose-dependent reductions in the prandial insulin dose and in fasting blood glucose, which decreased to 60-100 mg/dl across dose levels. Within-patient variability was <14 and <26% for the area under the concentration versus time curve (AUC) of the 8-point blood glucose profile and fasting blood glucose, respectively. The nocturnal glucose control between 03:00 and 09:00 hours was relatively unchanged. Mild hypoglycaemia was the most common adverse event.

Conclusions: In this Phase I study of fixed LY2605541 doses without titration, LY2605541 was well-tolerated and demonstrated a flat PK and GD profile accompanied by glucose normalization, prandial insulin dose reduction and no severe hypoglycaemia.

Keywords: insulin analogues; pharmacodynamics; pharmacokinetics; type 2 diabetes.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Area Under Curve
  • Blood Glucose / drug effects*
  • Blood Glucose / metabolism
  • C-Peptide / drug effects*
  • C-Peptide / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Drug Administration Schedule
  • Female
  • Glucose Clamp Technique
  • Glycated Hemoglobin A / drug effects*
  • Glycated Hemoglobin A / metabolism
  • Humans
  • Hypoglycemia / chemically induced
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacokinetics*
  • Insulin Lispro / administration & dosage
  • Insulin Lispro / pharmacokinetics*
  • Male
  • Middle Aged
  • Polyethylene Glycols / administration & dosage
  • Polyethylene Glycols / pharmacokinetics*
  • Treatment Outcome

Substances

  • Blood Glucose
  • C-Peptide
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Insulin Lispro
  • LY2605541
  • hemoglobin A1c protein, human
  • Polyethylene Glycols