Pharmacology: Pharmacodynamics: Mechanism of action: Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from the gastrointestinal tract in response to a meal. Incretin hormones regulate plasma glucose levels by stimulating glucose-dependent insulin release from pancreatic beta cells and inhibiting glucagon secretion from pancreatic alpha cells. The enzyme Dipeptidyl Peptidase IV (DPP-4) however, rapidly degrades both GLP-1 and GIP within a few minutes. Teneligliptin exerts its hypoglycemic action by suppressing the degradation of GLP-1 via inhibition of dipeptidyl peptidase-4 (DPP-4) enzymes thereby increasing blood concentrations of active GLP-1. Teneligliptin inhibits human plasma DPP-4 activity in a concentration-dependent manner with an in vitro IC50 value (95% confidence interval) of 1.75 (1.62-1.89) nmol/L.
In subjects with Type 2 diabetes, Teneligliptin 20 mg once daily inhibits DPP-4 activity by 89.7% 2 hours after oral administration and by 61.8% 24-hours post dose. Teneligliptin 20 mg once daily in the morning significantly increases plasma GLP-1 and significantly decreases plasma glucagon levels after breakfast, lunch and dinner. Once daily morning administration of Teneligliptin 20 mg improves fasting blood glucose levels and 2 hr post prandial blood glucose levels after each meal (breakfast, lunch and dinner).
Pharmacokinetics: Teneligliptin is rapidly absorbed. Peak Teneligliptin plasma concentrations (T
max) occur 1.8 hrs and 1 hr after single oral administration of a 20 mg and 40 mg dose, respectively. Plasma AUC
0-inf of Teneligliptin increases in a dose proportional manner; following single oral 20 mg and 40 mg dose in healthy volunteers, mean plasma AUC
0-inf of Teneligliptin was 2,028.9 ng.hr/mL and 3,705.1 ng.hr/mL, C
max was 187.2 ng/mL and 382.4 ng/mL, and apparent terminal half-life (t
1/2) was 24.2 and 20.8 hrs, respectively (see Table 1).
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Plasma C
max, AUC
0-inf of Teneligliptin increases at steady-state compared to the first dose (see Table 2).
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Coadministration of Teneligliptin with food reduces C
max by 20%, increases T
max from 1.1 to 2.6 hours but does not affect AUC
0-inf of Teneligliptin compared with coadministration without food (fasting state). This change is not clinically meaningful. Teneligliptin can be taken before or after a meal, however administration 1 hour before a meal is preferable (see Table 3). The plasma protein binding rate is 77.6 - 82.2%.
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Metabolism: After a single oral dose of [14C]-labeled Teneligliptin 20 mg, 5 metabolites, M1, M2, M3, M4, and M5, are observed in plasma.
In-vitro studies indicate that CYP3A4 and flavin-containing monooxygenase 3 (FMO3) are the major and CYP2D6 and flavin-containing monooxygenase 1 (FMO1) are the minor enzymes responsible for the metabolism of Teneligliptin. In addition, Teneligliptin is a weak inhibitor of CYP2D6, CYP3A4, and FMO; IC50 values: 489.4, 197.5 and 467.2 µmol/L, respectively. In vitro Teneligliptin does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C8/9, CYP2C19, and CYP2E1. Teneligliptin does not induce CYP1A2 and CYP3A4.
Excretion: Two hundred and sixteen (216) hours after a single 20 mg oral dose of [14C] Teneligliptin, 45.4% of the administered radioactivity was excreted in urine and 46.5% in feces. Approximately 21.5% of an oral dose of Teneligliptin is excreted unchanged in the urine. The renal clearance rate for Teneligliptin is 37-39 mL/hr/kg. The cumulative urinary excretion rates 120 hrs post dose for un-metabolized, M1, M2, and M3 were 14.8%, 17.7%, 1.4% and 1.9% respectively while the cumulative fecal excretion rates 120 hrs post dose for un-metabolized, M1, M3, M4 and M5 were 26.1%, 4.0%, 1.6%, 0.3% and 1.3% respectively.
Renal Impairment: Compared with healthy adult subjects, C
max and t
1/2 are not significantly changed in subjects with mild (50≤CrCl≤80 mL/min), moderate (30≤CrCl<50 mL/min), or severe (CrCl<30 mL/min) renal impairment (see Table 4). AUC
0-inf, significantly increases 1.25-fold, 1.68-fold, and 1.49-fold in subjects with mild, moderate, and severe renal impairment, respectively, relative to healthy adult subjects. Compared with healthy adult subjects, C
max and t
1/2 are not significantly changed in subjects with end stage failure but AUC
0-inf increases 1.16-fold (see Table 5). Renal impairment does not have a clinically meaningful effect on the pharmacokinetics of Teneligliptin, dose adjustments are not required in subjects with any degree of renal impairment.
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Hepatic Impairment: Compared with healthy adult subjects, C
max and t
1/2 are not significantly increased in subjects with mild (Child-Pugh Score 5-6) and moderate hepatic impairment (Child-Pugh Score 7-9), see Table 6. AUC
0-inf is however increased 1.46-fold and 1.59-fold in subjects with mild and moderate hepatic impairment, respectively. Mild to moderate hepatic impairment does not have a clinically meaningful effect on the pharmacokinetics of Teneligliptin, dose adjustments are not required in subjects with mild to moderate hepatic impairment. There is no clinical experience with Teneligliptin in patients with severe hepatic impairment (Child-Pugh Score > 9).
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Elderly: The pharmacokinetics of Teneligliptin in healthy elderly subjects (>65 years of age) is not significantly different compared to healthy non-elderly subjects (age < 65 years of age); geometric least mean square ratio (elderly: non-elderly) of C
max, AUC
0-inf, and t
1/2 are 1.006 (0.871-1.163), 1.090 (0.975-1.218) and 1.054 (0.911-1.219), respectively. No dosage adjustment is required in elderly subjects.
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