Tirzepatide is a long acting GIP and GLP-1 receptor agonist. Both receptors are present on the pancreatic α and β endocrine cells, heart, vasculature, immune cells (leukocytes), gut and kidney. GIP receptors are also present on adipocytes.
In addition, both GIP and GLP-1 receptors are expressed in the areas of the brain important to appetite regulation.
Tirzepatide is highly selective to human GIP and GLP-1 receptors. Tirzepatide has high affinity to both the GIP and GLP-1 receptors. The activity of tirzepatide on the GIP receptor is similar to native GIP hormone. The activity of tirzepatide on the GLP-1 receptor is lower compared to native GLP-1 hormone.
Tirzepatide improves glycaemic control by lowering fasting and postprandial glucose concentrations in patients with type 2 diabetes through several mechanisms.
Tirzepatide lowers body weight and body fat mass. The mechanisms associated with body weight and body fat mass reduction involve decreased food intake through the regulation of appetite. Clinical studies show that tirzepatide reduces energy intake and appetite by increasing feelings of satiety and fullness, and decreasing feelings of hunger.
Tirzepatide increases pancreatic β-cell glucose sensitivity. It enhances first- and second-phase insulin secretion in a glucose dependent manner.
In a hyperglycaemic clamp study in patients with type 2 diabetes, tirzepatide was compared to placebo and the selective GLP-1 receptor agonist semaglutide 1 mg for insulin secretion. Tirzepatide 15 mg enhanced the first and second-phase insulin secretion rate by 466% and 302% from baseline, respectively. There was no change in first- and second-phase insulin secretion rate for placebo.
Tirzepatide improves insulin sensitivity.
Tirzepatide 15 mg improved whole body insulin sensitivity by 63%, as measured by M-value, a measure of glucose tissue uptake using hyperinsulinemic euglycaemic clamp. The M-value was unchanged for placebo.
Tirzepatide lowers body weight in patients with obesity and overweight, and in patients with type 2 diabetes (irrespective of body weight), which may contribute to improvement in insulin sensitivity. Reduced food intake with tirzepatide contributes to body weight loss. The body weight reduction is mostly due to reduced fat mass.
Tirzepatide reduced the fasting and postprandial glucagon concentrations in a glucose dependent manner. Tirzepatide 15 mg reduced fasting glucagon concentration by 28% and glucagon AUC after a mixed meal by 43%, compared with no change for placebo.
Tirzepatide delays gastric emptying which may slow post meal glucose absorption and can lead to a beneficial effect on postprandial glycaemia. Tirzepatide induced delay in gastric emptying diminishes over time.
Tirzepatide consists of 39-amino acids and has a C20 fatty diacid moiety attached, which enables albumin binding and prolongs half-life.
Maximum concentration of tirzepatide is reached 8 to 72 hours post dose. Steady state exposure is achieved following 4 weeks of once weekly administration. Tirzepatide exposure increases in a dose proportional manner.
Similar exposure was achieved with subcutaneous administration of tirzepatide in the abdomen, thigh, or upper arm.
Absolute bioavailability of subcutaneous tirzepatide was 80%.
The mean apparent steady-state volume of distribution of tirzepatide following subcutaneous administration in patients with type 2 diabetes is approximately 10.3 L, and 9.7 L in patients with obesity.
Tirzepatide is highly bound to plasma albumin (99%).
Tirzepatide is metabolised by proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid moiety and amide hydrolysis.
The apparent population mean clearance of tirzepatide is approximately 0.06 L/h with an elimination half-life of approximately 5 days, enabling once weekly administration.
Tirzepatide is eliminated by metabolism. The primary excretion routes of tirzepatide metabolites are via urine and faeces. Intact tirzepatide is not observed in urine or faeces.
Age, gender, race, ethnicity, or body weight, do not have a clinically relevant effect on the pharmacokinetics (PK) of tirzepatide. Based on a population PK analysis, the exposure of tirzepatide increases with decreasing body weight; however, the effect of body weight on the PK of tirzepatide does not appear to be clinically relevant.
Renal impairment does not impact the PK of tirzepatide. The PK of tirzepatide after a single 5 mg dose was evaluated in patients with different degrees of renal impairment (mild, moderate, severe, ESRD) compared with subjects with normal renal function and no clinically relevant differences were observed. This was also shown for patients with both type 2 diabetes mellitus and renal impairment based on data from clinical studies.
Hepatic impairment does not impact the PK of tirzepatide. The PK of tirzepatide after a single 5 mg dose was evaluated in patients with different degrees of hepatic impairment (mild, moderate, severe) compared with subjects with normal hepatic function and no clinically relevant differences were observed.
Tirzepatide has not been studied in paediatric patients.
Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology or repeat-dose toxicity or genotoxicity.
A 2-year carcinogenicity study was conducted with tirzepatide in male and female rats at doses of 0.15, 0.50, and 1.5 mg/kg (0.12, 0.36, and 1.02-fold the maximum recommended human dose (MRHD) based on AUC) administered by subcutaneous injection twice weekly. Tirzepatide caused an increase in thyroid C-cell tumours (adenomas and carcinomas) at all doses compared to controls. The human relevance of these findings is unknown.
In a 6-month carcinogenicity study in rasH2 transgenic mice, tirzepatide at doses of 1, 3, and 10 mg/kg administered by subcutaneous injection twice weekly did not produce increased incidences of thyroid C-cell hyperplasia or neoplasia at any dose.
Animal studies with tirzepatide did not indicate direct harmful effects with respect to fertility.
In animal reproduction studies, tirzepatide caused foetal growth reductions and foetal abnormalities at exposures below the MRHD based on AUC. An increased incidence of external, visceral, and skeletal malformations and visceral and skeletal developmental variations were observed in rats. Foetal growth reductions were observed in rats and rabbits. All developmental effects occurred at maternally toxic doses.
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