Mechanism of Action

●    Teneligliptin inhibited human dipeptidyl peptidase-4 (DPP-4) enzyme activity with the IC₅₀=1 nM, more than 150 fold selectivity against DPP-8 and DPP-9 which suggested little off-target skin lesion side effect^{[1,2,3,4,5,6,7]}.

●    By DPP-4 inhibition, teneligliptin prevented the degradation of incretins GLP-1, GIP and promoted insulin release which prevented blood glucose increase after food intake with little hypoglycemia risk during lifetime taken^[8,9,10,11].

In Vivo Efficacy

●    DPP-4 inhibition: Zucker fatty rats: 0.1 mg/kg.

●    Insulin increased after OGTT: Zucker fatty rats: 0.1 mg/kg.

●    Blood glucose concentration decreased after OGTT: Zucker fatty rats: 0.03 mg/kg and KK-Ay mice: 0.3 mg/kg.

●    Teneligliptin did not decrease blood glucose level in fast Wistar rats.

Absorption

●    Dose dependent parmacokinetics: following a single oral dose administration at 0.1- 1 mg/kg, in rats C_max increase was super proportional over the oral dose and AUC_inf proportionally increased with increasing dose, in monkeys C_max proportionality increased with dose and AUC_inf increased less dose rate.

●    Oral bioavailability was good in rats (62.9-85.9 %) and monkeys (44.1-83.2 %).

●    Teneligliptin was rapidly absorbed after oral administration, with T_max occurring 0.75 hr to 1.38 hrs postdose, then biphase elimination in non-clinical species and humans.

●    Half-life of teneligliptin was long in the rats, monkeys and humans (8.43 - 24.2 hrs) with clearance well below 30% hepatic blood flow in rats and monkeys.

●    The steady state distribution volume (Vd_ss) in rats and monkeys was 8.906 L/kg and 4.802 L/kg respectively, which was larger than body water volume, indicating large distribution into peripheral tissues.

Distribution

●    The plasma protein binding of teneligliptin was moderate in mice (72.1-75.5 %), rats (62.5-68.2 %), rabbits (87.1 -88.5 %), dogs (63.8-68.7 %), monkeys (74.9-79.3 %) and humans (77.6-82.2%). The partition coefficient of RBC to plasma was less than 1, thus dose not significantly penetrate into red blood cells. In human plasma, teneligliptin was mainly bound to HSA and α1-AGP.

●    In SD rats, radioactivity was rapidly distributed in all organs examined (T_max=0.5 hr), with highest concentrations in GI, kidney and liver, lowest concentration in brain after single oral dose administration of [¹⁴C] teneligliptin and the elimination of radioactivity was slow.

●    In Brown Norway rats, the elimination of radioactivity in eye and skin was slower than in SD rats and other tissues after single oral dose administration of [¹⁴C] teneligliptin, which suggested teneligliptin having affinity for melanin.

Metabolite

●    In vitro metabolism study, M1 was a major metabolite rats, monkeys and human liver microsomes.

●    After a single oral dose administration, metabolites (M1 M2, M3, M4 and M5) identified in human plasma also presented in non-clinical species plasma.

v    After an oral dose administration, parent (a major component in plasma) accounted for 32.7 to 86.7 % of total radioactivity in human and non-clinical species plasma.

v    M1 was the major metabolite in plasma, accounting for 3.8 %, 10.0 % and 15.1 % in rats, monkeys and humans, respectively, following an oral dose administration.

●    Metabolic enzymes of teneligliptin were CYP3A4, FMO1 and FMO3.

●    Metabolites M1, M2, M3, M4, M5 had inhibitory effects on DPP-4 with IC50 = 34.3, 35.7, 0.951, 5.06 nM respectively. M3 did not show any DPP-4 inhibitory effect up to 1000 nM.

Excretion

●    In rats and monkeys, the predominant excretion route following single oral administration was feces (>60%) via bile, the major component in rat urine and feces was the parent, in monkey urine and feces was M1 and M3 respectively.

●    In humans, equal amounts were excreted urine (M1) and feces (teneligliptin).

Drug-Drug Interaction

●    Teneligliptin was not an inducer of CYP1A2, 3A4 and weakly inhibited CYP 3A4, CYP2D6 and FMO.

●    Teneligliptin was a P-gp substrate, the %inhibition of P-gp was 42.5% at the concentration of 99 μM.

●    Teneligliptin showed no inhibitory effects on the transport of a specific substrate of OCT2 and OAT1. On the other hand, the inhibitory effect was observed for the transport of specific substrates of OAT3, IC50 value was 99.2 μM.

Single Dose Toxicity

●    Single dose oral administration of teneligliptin in different species:

●    Rats MTD: 1000 mg/kg.

●    Monkeys MTD: 1000 mg/kg.

Repeated Dose Toxicity

●    Repeated dose oral administration of teneligliptin in different species from 13 to 52 weeks.

●    For rats, NOAELs were 10 mg/kg (4× and 3×MRHD for male and female respectively), determined by 26-weeks repeated dose toxicity, toxicity including minor high white blood cell counts.

●    For monkeys, NOAEL was 30 mg/kg (24× and 14×MRHD for male and female respectively), determined by 52-weeks repeated dose toxicity, toxicity including skin lesions and QT and QTc prolongation.

●    Common changes in rats and monkeys was histopathological changes in the stomach and intestinal.

Safety Pharmacology

●    No effects on the central nervous system, respiratory system and renal/urinary system at up to 100 mg/kg in rats.

●    Teneligliptin inhibited gastric emptying in rats at 100 mg/kg.

●    Teneligliptin inhibited hERG potassium current: IC₅₀=3.45 µM, M1 weakly inhibited hERG potassium current: IC₅₀>100 μM.

●    ADP₉₀ and ADP₅₀ extended in isolated guinea pig papillary muscle.

●    Significantly prolonged the effective refractory period and QTc, MAP₉₀ at 7 mg/kg in anesthetized dogs.

●    Prolonged QTc and QT interval transiently upon oral administration of 30 mg/kg in conscious monkeys.

Genotoxicity

●    Teneligliptin: negative.

●    Metabolites M1 and M2: increase frequency of chromosome structural aberration at 3750 and 3500 μg/mL without S9 activation, respectively.

Reproductive and Developmental Toxicity

●    Rats fertility toxicity: NOAELs were 70 and 100 mg/kg (11< and 45×MRHD) for male and female respectively.

●    Fetal embryonic developmental toxicity: NOAEL was 30 mg/kg (11 and 16 ×MRHD for rats and rabbits, respectively).

●    Postnatal developmental toxicity: NOAEL was 30 mg/kg (11×MRHD).

●    Teneligliptin distributed to tissues including placenta and fetus in pregnant rats, but the amount of radioactivity C_max in fetus was less than 0.05% of the administered radioactivity.

●    Milk excretion of teneligliptin was also found in lactating rats and excretion ratio was: milk/plasma=1.00 (AUC_inf), 0.92 (C_max).

Carcinogenicity

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

●    For mice, NOAEL for tumor was 600 mg/kg (118× and 126×MRHD for male and female respectively). NOAEL for non-neoplastic lesions was 60 mg/kg (5× and 4×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).