Tolerability, pharmacokinetics and pharmacodynamics of the once-daily human GLP-1 analog liraglutide in Japanese healthy subjects: a randomized, double-blind, placebo-controlled dose-escalation study.
OBJECTIVE
Liraglutide is a once-daily human GLP-1 analog being developed as a Type 2 diabetes therapy. A dose-finding study in Japanese patients with Type 2 diabetes showed liraglutide to produce dose-dependent decreases in HbA(1C). Studies have also shown that, with stepped dose titration, liraglutide is well tolerated. This double-blind trial in 24 healthy Japanese men assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of once-daily subcutaneous (s.c.) liraglutide using doses exceeding those previously studied, and using the stepped titration approach.


METHODS
Subjects were randomized to three groups in each of which 6 received liraglutide, and 2 placebo for 35 consecutive days. The daily dose of liraglutide was stepped from 5 microg/kg (s.c. abdomen, morning) to 10 and then 15 microg/kg at 7-day intervals. One group remained at this dose, the others titrating further to 20 and 25 microg/kg, respectively. Subjects remained at the study site from Day 21 until the end of the trial, with standard meals served during inhouse periods.


RESULTS
No safety issues, hypoglycemia, gastrointestinal or any other adverse events were observed. Liraglutide showed dose-dependent increases in the pharmacokinetic parameters of AUC0-24 h, C(max) and C(trough), while t(max), t(1/2) and V(d/F) were constant. Mean plasma glucose concentrations were similar across all treatment groups at baseline, but dose-dependent decreases in mean and postprandial plasma glucose were seen with liraglutide, although all values remained within normal ranges. There was a tendency for weight to decrease with liraglutide in comparison to placebo.


CONCLUSIONS
Liraglutide appears to be well tolerated at doses of up to 25 microg/kg in Japanese subjects. Despite clear pharmacodynamic effects in this euglycemic cohort, a low risk for hypoglycemia was suggested together with good gastrointestinal tolerability.
Kyushu Clinical Pharmacology Research Clinic, Fukuoka, Japan. shin-irie@lta-med.com
S
S
Irie
Y
Y
Matsumura
M
M
Zdravkovic
L V
LV
Jacobsen
S
S
Kageyama
D000328:Adult; D019540:Area Under Curve; D001786:Blood Glucose / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007279:Injections, Subcutaneous; D007564:Japan; D000069450:Liraglutide; D008297:Male; D008875:Middle Aged; D014018:Tissue Distribution; D015431:Weight Loss / Q000187:drug effects
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1