New Drug Update 2009-2010 - LAFP

Liraglutide – Victoza by Novo-Nordisk
INDICATIONS: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct
to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Important Limitations of Use:
•Not recommended as first-line therapy for patients inadequately controlled on diet and exercise.
•Has not been studied sufficiently in patients with a history of pancreatitis. Use caution.
•Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
•Has not been studied in combination with insulin.
CLINICAL PHARMACOLOGY: Liraglutide is a human analog of the glucagon-like peptide-1 (GLP-1) with
97% amino acid sequence homology to endogenous human GLP-1. It differs from human GLP-1 by the
addition of a C14 fatty acid. As a GLP-1 analog, it induces its activity through a glucose-dependent
stimulation of insulin secretion, inhibition of glucagon secretion, slowing of gastric emptying, and
reduction in appetite. Liraglutide also improves beta cell function in patients with type 2 diabetes.
GLP-1 has a half-life of 1.5-2 minutes due to degradation by the ubiquitous endogenous enzymes,
dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidases (NEP). Unlike native GLP-1, liraglutide is
stable against metabolic degradation by both peptidases and has a plasma half-life of 13 hours after
subcutaneous administration. The pharmacokinetic profile of liraglutide, which makes it suitable for once
daily administration, is a result of self-association that delays absorption, plasma protein binding and
stability against metabolic degradation by DPP-IV and NEP.
Fasting and postprandial glucose was measured before and up to 5 hours after a standardized meal after
treatment to steady state with 0.6, 1.2 and 1.8 mg liraglutide or placebo. Compared to placebo, the
postprandial plasma glucose AUC0-300min was 35% lower after liraglutide 1.2 mg and 38% lower after
liraglutide 1.8 mg.
PHARMACOKINETICS: Liraglutide is slowly absorbed following subcutaneous administration, reaching
peak levels at 9 to 12 hours after dosing. Absolute bioavailability is 51%. Pharmacokinetics were similar
with administration in the upper arm, abdomen, and thigh. A dose-proportional increase in exposure was
observed with increasing doses over a dose range of 1.25 to 12.5 mcg/kg.
Liraglutide 20 mcg/kg administered once daily subcutaneously exhibited less peak to trough variation
than exenatide 10 mcg/kg administered twice daily subcutaneously.
Liraglutide has a half-life of 11 to 15 hours following subcutaneous administration; allowing for once daily
subcutaneous administration. Liraglutide is metabolized to a number of minor metabolites, which are
excreted in the urine and feces. Liraglutide excretion in the urine is negligible.
Liraglutide pharmacokinetics were not substantially altered in subjects with renal function impairment,
including subjects with severe renal function impairment (creatinine clearance less than 30 mL/min) or
end-stage renal disease requiring dialysis. Liraglutide is not significantly removed by dialysis. Liraglutide
exposure appears to be reduced in patients with hepatic function impairment. Patients with renal or
hepatic function impairment should be dosed according to their glycemic control.
Elderly -Age had no effect on the pharmacokinetics of liraglutide based on a pharmacokinetic study in
healthy elderly subjects (65 to 83 years) and population pharmacokinetic analyses of patients 18 to 80
years of age.
Gender -Based on the results of population pharmacokinetic analyses, females have 34% lower weightadjusted
clearance of liraglutide compared to males. Based on the exposure response data, no dose
adjustment is necessary based on gender.
Race and Ethnicity -Race and ethnicity had no effect on the pharmacokinetics of liraglutide based on the
results of population pharmacokinetic analyses that included Caucasian, Black, Asian and Hispanic/Non-
Hispanic subjects.
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