Pharmacokinetics and tolerability of a novel long-acting glucagon-like peptide-1 analog, CJC-1131, in healthy and diabetic subjects

Int J Clin Pharmacol Ther. 2008 Sep;46(9):443-52. doi: 10.5414/cpp46443.

Abstract

Objective: The safety, tolerability, pharmacokinetics and preliminary pharmacodynamics of single rising doses of a novel GLP-1 analog, CJC-1131, was evaluated.

Methods: CJC-1131 was subcutaneously injected in 8 groups (1.5 - 20.5 microg/kg) of healthy subjects (each group of six subjects included 1 placebo per dose level). CJC-1131 was also injected subcutaneously in 6 groups (1.5 - 12 microg/kg) of Type 2 diabetic patients after a 9-day washout period from their own anti-diabetic medication. Each group of 8 patients included 2 placebo-treated patients. Seven blood glucose measurements were taken daily, and meal tolerance tests were performed on the day before dosing and on Day 3.

Results: CJC-1131 was quickly absorbed from the subcutaneous space, and a less than dose-proportional increase was found in Cmax. The half-life of CJC-1131 varied from 8.9 - 14.7 days in healthy subjects and from 9.1 - 13.8 days in patients. The maximum tolerated dose in healthy subjects was established at 12 microg/kg with nausea and vomiting being the dose-limiting events. These events occurred generally in the morning after dosing. Blood glucose levels in patients decreased on Day 1 in proportion with dose, with a maximum average decrease of 4.1 mmol/l in the highest dose group. Higher doses appeared to be related to a slight weight loss in patients.

Conclusions: Conjugation to albumin led to a major prolongation of the half-life of GLP-1. The tolerability of this potential antidiabetic drug seems to be limited only by gastrointestinal complaints.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Blood Glucose / drug effects
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Glucagon-Like Peptide 1 / analogs & derivatives
  • Half-Life
  • Humans
  • Hypoglycemic Agents / administration & dosage*
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / pharmacokinetics
  • Injections, Subcutaneous
  • Male
  • Maleimides / administration & dosage*
  • Maleimides / adverse effects
  • Maleimides / pharmacokinetics
  • Maximum Tolerated Dose
  • Middle Aged
  • Nausea / chemically induced
  • Peptides / administration & dosage*
  • Peptides / adverse effects
  • Peptides / pharmacokinetics
  • Protein Binding
  • Serum Albumin / metabolism
  • Vomiting / chemically induced

Substances

  • Blood Glucose
  • CJC 1131
  • Hypoglycemic Agents
  • Maleimides
  • Peptides
  • Serum Albumin
  • Glucagon-Like Peptide 1