Combination of two active substances with complementary mechanisms of action to improve glycaemic control: insulin glargine, a basal insulin analogue (mainly targeting fasting plasma glucose), and lixisenatide, a GLP-1 receptor agonist (mainly targeting postprandial glucose).
The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogues lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis and enhances protein synthesis.
Lixisenatide is a 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 beta cells and suppresses glucagon from alpha cells in the pancreas.
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. A preprandial injection of Lixisenatide also slows gastric emptying thereby reducing the rate at which meal-derived glucose is absorbed and appears in the circulation.
The combination of insulin glargine and lixisenatide has no impact on the pharmacodynamics of insulin glargine. The impact of the combination of insulin glargine and lixisenatide on the pharmacodynamics of lixisenatide has not been studied in phase 1 studies.
Consistent with a relatively constant concentration/time profile of insulin glargine over 24 hours with no pronounced peak when administered alone, the glucose utilisation rate/time profile was similar when given in the insulin glargine/lixisenatide combination.
The time course of action of insulins, including insulin glargine/lixisenatide, may vary between individuals and within the same individual.
In clinical studies with insulin glargine (100 units/ml) the glucose-lowering effect on a molar basis (i.e., when given at the same doses) of intravenous insulin glargine is approximately the same as that for human insulin.
In a 28-day placebo-controlled study in patients with type 2 diabetes 5 to 20 mcg lixisenatide resulted in a statistically significant decreases in postprandial blood glucose after breakfast, lunch and dinner.
Following a standardised labelled test meal, in the study referred to above, it was confirmed that lixisenatide slows gastric emptying, thereby reducing the rate of postprandial glucose absorption. The slowing effect of gastric emptying was maintained at the end of the study.
The insulin glargine/lixisenatide ratio has no relevant impact on the PK of insulin glargine and lixisenatide in insulin glargine/lixisenatide fixed dose combination.
After subcutaneous administration of insulin glargine/lixisenatide combinations to patients with type 1 diabetes, insulin glargine showed no pronounced peak. Exposure to insulin glargine following administration of the insulin glargine/lixisenatide combination was 86-88% compared to administration of separate simultaneous injections of insulin glargine and lixisenatide. This difference is not considered clinically relevant.
After subcutaneous administration of insulin glargine/lixisenatide combinations to patients with type 1 diabetes, the median tmax of lixisenatide was in the range of 2.5 to 3.0 hours. AUC was comparable while there was a small decrease in Cmax of lixisenatide of 22-34% compared with separate simultaneous administration of insulin glargine and lixisenatide, which is not likely to be clinically significant.
There are no clinically relevant differences in the rate of absorption when lixisenatide as monotherapy is administered subcutaneously in the abdomen, deltoid, or thigh.
The apparent volume of distribution of insulin glargine after subcutaneous administration of the insulin glargine/lixisenatide combinations (Vss/F) is approximately 1700 L.
Lixisenatide has a low level (55%) of binding to human proteins. The apparent volume of distribution of lixisenatide after subcutaneous administration of insulin glargine/lixisenatide combinations (Vz/F) is approximately 100 L.
A metabolism study in diabetic patients who received insulin glargine alone indicates that insulin glargine is rapidly metabolised at the carboxyl terminus of the B chain to form two active metabolites, M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin). In plasma, the principal circulating compound is the metabolite M1. The pharmacokinetic and pharmacodynamic findings indicate that the effect of the subcutaneous injection with insulin glargine is principally based on exposure to M1.
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 single subcutaneous administration of the insulin glargine/lixisenatide combination, the mean apparent clearance (CL/F) of insulin glargine was approximately 120 L/h.
After multiple-dose subcutaneous administration of Lixisenatide 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.
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 of lixisenatide was increased by 46%, 51% and 87%, respectively.
Insulin glargine has not been studied in patients with renal impairment. In patients with renal impairment, however, insulin requirements may be diminished due to reduced insulin metabolism.
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.
Insulin glargine has not been studied in diabetes patients with hepatic impairment. In patients with hepatic impairment, insulin requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism.
Insulin glargine: Effect of age, race, and gender on the pharmacokinetics of insulin glargine has not been evaluated. In controlled clinical studies in adults with insulin glargine (100 units/ml), subgroup analyses based on age, race, and gender did not show differences in safety and efficacy.
Lixisenatide: 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.
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.
Gender has no clinically relevant effect on the pharmacokinetics of lixisenatide
Body weight has no clinically relevant effect on lixisenatide AUC.
In the presence of anti-lixisenatide antibodies, lixisenatide exposure and variability in exposure are markedly increased regardless of the dose level.
No studies have been performed with insulin glargine/lixisenatide combination in children and adolescents below 18 years of age.
No animal studies have been conducted with the combination of insulin glargine and lixisenatide to evaluate repeated dose toxicity, carcinogenesis, genotoxicity, or toxicity to reproduction.
Non-clinical data for insulin glargine reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
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.
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