Chemical formula: C₁₇₂H₂₆₅N₄₃O₅₁ Molecular mass: 3,749.95 g/mol
Liraglutide is a GLP-1 analogue with 97% sequence homology to human GLP-1 that binds to and activates the GLP-1 receptor. The GLP-1 receptor is the target for native GLP-1, an endogenous incretin hormone that potentiates glucose-dependent insulin secretion from the pancreatic beta cells. Unlike native GLP-1, liraglutide has a pharmacokinetic and pharmacodynamic profile in humans suitable for once daily administration. Following subcutaneous administration, the protracted action profile is based on three mechanisms: self-association, which results in slow absorption; binding to albumin; and higher enzymatic stability towards the dipeptidyl peptidase -4 (DPP-4) and neutral endopeptidase (NEP) enzymes, resulting in a long plasma half-life.
Liraglutide action is mediated via a specific interaction with GLP-1 receptors, leading to an increase in cyclic adenosine monophosphate (cAMP). Liraglutide stimulates insulin secretion in a glucosedependent manner. Simultaneously, liraglutide lowers inappropriately high glucagon secretion, also in a glucose-dependent manner. Thus, when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. Conversely, during hypoglycaemia liraglutide diminishes insulin secretion and does not impair glucagon secretion. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying. Liraglutide reduces body weight and body fat mass through mechanisms involving reduced hunger and lowered energy intake, GLP-1 is a physiological regulator of appetite and food intake, but the exact mechanism of action is not entirely clear.
In animal studies, peripheral administration of liraglutide led to uptake in specific brain regions involved in regulation of appetite, where liraglutide via specific activation of the GLP-1 receptor (GLP-1R) increased key satiety and decreased key hunger signals, thereby leading to lower body weight.
GLP-1 receptors are also expressed in specific locations in the heart, vasculature, immune system, and kidneys. In mouse models of atherosclerosis, liraglutide prevented aortic plaque progression and reduced inflammation in the plaque. In addition, liraglutide had a beneficial effect on plasma lipids. Liraglutide did not reduce the plaque size of already established plaques.
Liraglutide has 24-hour duration of action and improves glycaemic control by lowering fasting and postprandial blood glucose in patients with type 2 diabetes mellitus.
The absorption of liraglutide following subcutaneous administration is slow, reaching maximum concentration 8–12 hours post dosing. Estimated maximum liraglutide concentration was 9.4 nmol/l for a subcutaneous single dose of liraglutide 0.6 mg. At 1.8 mg liraglutide, the average steady state concentration of liraglutide (AUCτ/24) reached approximately 34 nmol/l. Liraglutide exposure increased proportionally with dose. The intra-subject coefficient of variation for liraglutide AUC was 11% following single dose administration. Absolute bioavailability of liraglutide following subcutaneous administration is approximately 55%.
The apparent volume of distribution after subcutaneous administration is 11–17 l. The mean volume of distribution after intravenous administration of liraglutide is 0.07 l/kg. Liraglutide is extensively bound to plasma proteins (>98%).
During 24 hours following administration of a single radiolabelled [3H]-liraglutide dose to healthy subjects, the major component in plasma was intact liraglutide. Two minor plasma metabolites were detected (≤9% and ≤5% of total plasma radioactivity exposure). Liraglutide is metabolised in a similar manner to large proteins without a specific organ having been identified as major route of elimination.
Following a [3H]-liraglutide dose, intact liraglutide was not detected in urine or faeces. Only a minor part of the administered radioactivity was excreted as liraglutide-related metabolites in urine or faeces (6% and 5%, respectively). The urine and faeces radioactivity was mainly excreted during the first 6–8 days, and corresponded to three minor metabolites, respectively.
The mean clearance following subcutaneous administration of a single dose liraglutide is approximately 1.2 l/h with an elimination half-life of approximately 13 hours.
Age had no clinically relevant effect on the pharmacokinetics of liraglutide based on the results from a pharmacokinetic study in healthy subjects and population pharmacokinetic data analysis of patients (18 to 80 years).
Gender had no clinically meaningful effect on the pharmacokinetics of liraglutide based on the results of population pharmacokinetic data analysis of male and female patients and a pharmacokinetic study in healthy subjects.
Ethnic origin had no clinically relevant effect on the pharmacokinetics of liraglutide based on the results of population pharmacokinetic analysis which included patients of White, Black, Asian and Hispanic groups.
Population pharmacokinetic analysis suggests that body mass index (BMI) has no significant effect on the pharmacokinetics of liraglutide.
The pharmacokinetics of liraglutide was evaluated in patients with varying degree of hepatic impairment in a single-dose trial. Liraglutide exposure was decreased by 13–23% in patients with mild to moderate hepatic impairment compared to healthy subjects.
Exposure was significantly lower (44%) in patients with severe hepatic impairment (Child Pugh score >9).
Liraglutide exposure was reduced in patients with renal impairment compared to individuals with normal renal function. Liraglutide exposure was lowered by 33%, 14%, 27% and 26% in patients with mild (creatinine clearance, CrCl 50–80 ml/min), moderate (CrCl 30–50 ml/min), and severe (CrCl <30 ml/min) renal impairment and in end-stage renal disease requiring dialysis, respectively.
Similarly, in a 26-week clinical trial, patients with type 2 diabetes and moderate renal impairment (CrCL 30–59 ml/min) had 26% lower liraglutide exposure when compared with a separate trial including patients with type 2 diabetes with normal renal function or mild renal impairment.
Pharmacokinetic properties were assessed in clinical studies in the paediatric population with type 2 diabetes aged 10 years and above. The liraglutide exposure in adolescents and children was comparable to that observed in the adult population.
Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeat-dose toxicity or genotoxicity.
Non-lethal thyroid C-cell tumours were seen in 2-year carcinogenicity studies in rats and mice. In rats, a no observed adverse effect level (NOAEL) was not observed. These tumours were not seen in monkeys treated for 20 months. These findings in rodents are caused by a non-genotoxic, specific GLP-1 receptor-mediated mechanism to which rodents are particularly sensitive. The relevance for humans is likely to be low but cannot be completely excluded. No other treatment-related tumours have been found.
Animal studies did not indicate direct harmful effects with respect to fertility but slightly increased early embryonic deaths at the highest dose. Dosing with liraglutide during mid-gestation caused a reduction in maternal weight and foetal growth with equivocal effects on ribs in rats and skeletal variation in the rabbit. Neonatal growth was reduced in rats while exposed to liraglutide, and persisted in the post-weaning period in the high dose group. It is unknown whether the reduced pup growth is caused by reduced pup milk intake due to a direct GLP-1 effect or reduced maternal milk production due to decreased caloric intake.
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