Lixisenatide

Lixisenatide is a selective GLP-1 receptor agonist. 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.

Lixisenatide action is mediated via a specific interaction with GLP-1 receptors, leading to an increase in intracellular cyclic adenosine monophosphate (cAMP). Lixisenatide stimulates insulin secretion when blood glucose is increased but not at normoglycaemia, which limits the risk of hypoglycaemia.

In parallel, glucagon secretion is suppressed. In case of hypoglycaemia, the rescue mechanism of glucagon secretion is preserved.

Lixisenatide slows gastric emptying thereby reducing the rate at which meal-derived glucose appears in the circulation.

Pharmacodynamic effects

When administered once daily, lixisenatide improves glycaemic control through the immediate and sustained effects of lowering both post-prandial and fasting glucose concentrations in patients with type 2 diabetes.

This effect on post-prandial glucose was confirmed in a 4-week study versus liraglutide 1.8 mg once a day in combination with metformin. Reduction from baseline in the AUC_0:30-4:30h of plasma glucose after a test-meal was: -12.61 h*mmol/L (-227.25 h*mg/dl) in the lixisenatide group and -4.04 h*mmol/L (-72.83 h*mg/dl) in the liraglutide group. This was also confirmed in an 8-week study versus liraglutide, administered before breakfast, in combination with insulin glargine with or without metformin.

Absorption

Following subcutaneous administration to patients with type 2 diabetes, the rate of lixisenatide absorption is rapid and not influenced by the dose administered. Irrespective of the dose and whether lixisenatide was administered as single or multiple doses, the median t_max is 1 to 3.5 hours in patients with type 2 diabetes. There are no clinically relevant differences in the rate of absorption when lixisenatide is administered subcutaneously in the abdomen, thigh, or arm.

Distribution

Lixisenatide has a moderate level of binding (55%) to human proteins. The apparent volume of distribution after subcutaneous administration of lixisenatide (Vz/F) is approximately 100 L.

Biotransformation and elimination

As a peptide, lixisenatide is eliminated through glomerular filtration, followed by tubular reabsorption and subsequent metabolic degradation, resulting in smaller peptides and amino acids, which are reintroduced in the protein metabolism.

After multiple dose administration in patients with type 2 diabetes, mean terminal half-life was approximately 3 hours and the mean apparent clearance (CL/F) about 35 L/h.

Special populations

Patients with renal impairment

In subjects with mild (creatinine clearance calculated by the Cockcroft-Gault formula 60-90 ml/min), moderate (creatinine clearance 30-60 ml/min) and severe renal impairment (creatinine clearance 15-30 ml/min), AUC was increased by 46%, 51% and 87%, respectively.

Patients with hepatic impairment

As lixisenatide is cleared primarily by the kidney, no pharmacokinetic study has been performed in patients with acute or chronic hepatic impairment. Hepatic dysfunction is not expected to affect the pharmacokinetics of lixisenatide.

Gender

Gender has no clinically relevant effect on the pharmacokinetics of lixisenatide.

Race

Ethnic origin had no clinically relevant effect on the pharmacokinetics of lixisenatide based on the results of pharmacokinetic studies in Caucasian, Japanese and Chinese subjects.

Elderly

Age has no clinically relevant effect on the pharmacokinetics of lixisenatide. In a pharmacokinetic study in elderly non-diabetic subjects, administration of lixisenatide 20 mcg resulted in a mean increase of lixisenatide AUC by 29% in the elderly population (11 subjects aged 65 to 74 years and 7 subjects aged ≥75 years) compared to 18 subjects aged 18 to 45 years, likely related to reduced renal function in the older age group.

Body weight

Body weight has no clinically relevant effect on lixisenatide AUC.

Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology and toxicology.

In 2-year subcutaneous carcinogenicity studies, non-lethal C-cell thyroid tumours were seen in rats and mice and are considered to be caused by a non-genotoxic GLP-1 receptor-mediated mechanism to which rodents are particularly sensitive. C-cell hyperplasia and adenoma were seen at all doses in rats and a no observed adverse effect level (NOAEL) could be not defined. In mice, these effects occurred at exposure ratio above 9.3-fold when compared to human exposure at the therapeutic dose. No C-cell carcinoma was observed in mice and C-cell carcinoma occurred in rats with an exposure ratio relative to exposure at human therapeutic dose of about 900-fold. In 2-year subcutaneous carcinogenicity study in mice, 3 cases of adenocarcinoma in the endometrium were seen in the mid dose group with a statistically significant increase, corresponding to an exposure ratio of 97-fold. No treatment-related effect was demonstrated.

Animal studies did not indicate direct harmful effects with respect to male and female fertility in rats. Reversible testicular and epididymal lesions were seen in dogs treated with lixisenatide. No related effect on spermatogenesis was seen in healthy men.

In embryo-foetal development studies, malformations, growth retardation, ossification retardation and skeletal effects were observed in rats at all doses (5-fold exposure ratio compared to human exposure) and in rabbits at high doses (32-fold exposure ratio compared to human exposure) of lixisenatide. In both species, there was a slight maternal toxicity consisting of low food consumption and reduced body weight. Neonatal growth was reduced in male rats exposed to high doses of lixisenatide during late gestation and lactation, with a slightly increased pup mortality observed.