Teneligliptin

Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, dipeptidyl peptidase-4 (DPP-4). The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production.

Teneligliptin acts as a competitive reversible inhibitor of DPP-4 and decreases the degradation of incretins, especially GLP-1, thereby improving hyperglycemia by stimulating insulin secretion and suppressing glucagon secretion in a glucose-dependent manner (no or negligible risk of hypoglycemia).

Teneligliptin is a potent, selective, and long-lasting DPP-4 inhibitor that has approximately 700- to 1500-fold greater affinity for DPP-4 than other DPP enzymes, such as DPP-8 and DPP-9. Teneligliptin inhibits recombinant human DPP-4 and human plasma DPP-4 in a concentrationdependent manner: concentrations producing half maximal inhibition (IC50) are 0.889 nmol/l and 1.75 nmol/l, respectively.

Teneligliptin binds with the S2 extensive subsite of DPP-4 via strong hydrophobic interactions mediated by an ‘anchor lock domain’. These interactions may be related to the stronger potency of DPP-4 inhibition and longer duration of action of teneligliptin.

Teneligliptin is a selective and long-acting inhibitor of DPP-4 enzyme. By DPP-4 inhibition, teneligliptin prevented the degradation of incretins (GLP-1 and GIP) and promote insulin release. By increasing incretin hormone levels, teneligliptin increases insulin secretion and thereby decreases fasting and postprandial plasma glucose levels. Teneligliptin may also reduce plasma triglyceride levels through a sustained increase in GLP-1 levels. Teneligliptin has antioxidative properties and has shown endothelial protective effects in several non-clinical and clinical studies.

Absorption

Teneligliptin shows dose-dependent increases in the maximal plasma concentration (C_max) and area under the plasma concentration-time curve (AUC). Peak plasma concentration i.e., C_max of teneligliptin 20 mg is 187.20 ng/ml and its T_max is 1.8 hours. After repeated doses of teneligliptin 20 or 80 mg, no remarkable changes observed in the pharmacokinetic profile of drug. Teneligliptin reaches steady state by day 7.

Effect of food

C_max decreases after a single dose of 20 mg of teneligliptin given after meal to the healthy adults compared to when given in fasting condition and T_max prolongs up to 2.6 hours; however, no difference observed in AUC.

Distribution

Plasma protein binding of teneligliptin is 77.6 to 82.2%.

Metabolism

Teneligliptin is metabolized in the liver. The most abundant metabolite found in plasma is a thiazolidine-1-oxide derivative (designated as M1, 14.7%). The main enzymes responsible for teneligliptin metabolism are cytochrome P450 (CYP) 3A4 and flavin containing monooxygenase 3 (FMO3), with equal contribution.

Excretion

Of total body clearance, about 34.4% of teneligliptin is excreted unchanged via the kidney and the remaining 65.6% teneligliptin is metabolized and eliminated via renal and hepatic excretion. When a single oral dose of 20 mg teneligliptin was given to the healthy adults, 45.4% of dosage was excreted in urine and 46.5% was excreted in feces up to 216 hours after administration. Mean elimination half-life (t_½) of teneligliptin is 24.2 hours. Because of its elimination via multiple pathways, teneligliptin is considered a suitable treatment option for patients with hepatic or renal impairment.

Animal Toxicology

Single Dose Toxicity

Single dose oral administration of teneligliptin in rats – Maximum tolerated dose (MTD) is 1000 mg/kg. Single dose oral administration of teneligliptin in monkeys – MTD is 1000 mg/kg.

Repeated Dose Toxicity

Repeated dose oral administration of teneligliptin in different species from 13 to 52 weeks. For rats, no-observed-adverse-effect levels (NOAELs) were 10 mg/kg (4- and 3-times of maximum recommended human dose – MRHD for male and female respectively), determined by 26-weeks repeated dose toxicity, toxicity including minor high white blood cell counts. A common change in rats and monkeys was histopathological changes in the stomach and intestine.

Genotoxicity

Teneligliptin does not cause genotoxicity. Metabolites M1 and M2 may increase frequency of chromosome structural aberration at 3750 and 3500 μg/ml respectively.

Reproductive and Developmental Toxicity

Fertility toxicity in rats

NOAELs were 70 and 100 mg/kg (11- and 45-times MRHD) for male and female respectively.

Fetal embryonic developmental toxicity

NOAEL was 30 mg/kg (11- and 16-times MRHD for rats and rabbits, respectively).

Postnatal developmental toxicity

NOAEL was 30 mg/kg (11-times MRHD). Teneligliptin distributed to tissues including placenta and fetus in pregnant rats, but the amount of drug in fetus was less than 0.05% of the administered dose.

Carcinogenicity

For rats, NOAELs for tumor were 75 and 100 mg/kg (65- and 76-times MRHD) for male and female respectively. NOAEL for non-neoplastic lesions was 10 mg/kg (76-times MRHD) including changes in lung and kidney.

For mice, NOAEL for tumor was 600 mg/kg (118- and 126-times MRHD for male and female respectively). NOAEL for non-neoplastic lesions was 60 mg/kg (5- and 4-times MRHD for male and female respectively), including localized hyperplasia of squamous epithelium in fore-stomach, diffusion hyperplasia of mucosal epithelium in bladder, diffuse hypertrophy of liver cells, spleen extra-medullary hematopoiesis enhancement, diffuse vacuolation of the bundle meshwork cells in the adrenal gland (males), gallbladder localized hyperplasia of mucosal epithelium (females).