Evogliptin

The glucagon-like peptide-1 (GLP-1) is secreted from alimentary canal in response to meal that promotes insulin secretion from pancreas and regulates blood sugar post meal by controlling glucagon secretion. Evogliptin exhibits a hypoglycemic effect by controlling the decomposition of GLP-1 by inhibiting dipeptidyl peptidase-4 (DPP-4) activity and thereby increasing blood concentration of active form GLP-1.

In accordance with the results from biochemical studies, it was demonstrated that evogliptin non-covalently binds to the catalytic site of human DPP4 enzyme in crystal structures complexed to human DPP4. ter-butoxy residue of evogliptin distinictively interacts with Arg125 of human DPP4 unlike sitagliptin and this hydrophobic interaction may contribute to the high binding affinity of evogliptin.

Evogliptin is a competitive and reversible inhibitor of dipeptidyl peptidase IV (DPP-IV). The inhibitory activity of evogliptin is about 10-fold compared to sitagliptin, also the selectivity of evogliptin for DPP-IV is 6,000-fold higher as compared to DPP8/9.

Pre-clinical studies on evogliptin demonstrated significant DPP-IV inhibitory activity, increased active plasma GLP1 level, reduced blood glucose excursion in a dose-dependent manner. By virtue of DPP-IV inhibitory effect, evogliptin exhibited significant improvement in the fasting and post-prandial blood glucose levels.

Comparisons of inhibitory potencies of Evogliptin and Sitagliptin against human plasma DPP4 activity:

Evogliptin is highly selective to DPP4 enzyme more than 6,000-fold against DPP4 closely-related enzymes, which was comparable or superior to those of Sitagliptin. Evogliptin is a selective DPP4 inhibitor and Evogliptin has little possibility of causing adverse events due to inhibition of DPP4 closely-related proteases.

The maximum Evogliptin concentrations (C_max) were observed at 3.0 to 5.5 hours (median value), and the average half-lives (t_1/2) were estimated to be 32.5 to 39.8 hours. The average C_max and AUC_last values increased as the dose increased while dose-dependent changes were not shown in T_max and t_1/2.

Multiple ascending dose (MAD) study: The maximum Evogliptin concentrations (C_max) were observed at 4.0 to 5.0 hours (median value) after the last administration of Evogliptin at 5, 10, and 20 mg (Day 10), and the average half-lives (t_½) were estimated to be 32.9 to 38.8 hours. Dose-dependent changes were not shown in T_max and t_½ while the average C_max,ss and AUC_216-249h,ss values increased as the doses increased. The accumulation ratios were 1.44, 1.38 and 1.50 at 5, 10, and 20 mg of Evogliptin, respectively.

The absolute bioavailability of Evogliptin was 50.247%. Plasma protein binding of Evogliptin is 46%.

In in vitro and in vivo metabolism study of Evogliptin in rat, dog, monkey, and human liver microsome, total seventeen kinds of metabolites were identified. Among them, M7 and M8 (mono-hydroxylated metabolites), and M16 (glucuronide metabolite) were major metabolites. CYP3A4 plays the major role in hydroxylation of Evogliptin to M7 and M8, and UGT2B7 plays the major role in the glucuronidation of M7 to M16.

In CYP inhibition assay in human liver microsome using in vitro cocktail of probe substrates, Evogliptin up to 50 μM did not show significant inhibition against activities of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4, suggesting the negligible CYP inhibition activity of the drug. In addition, it was found that Evogliptin has negligible potential of CYP1A2, 2B6 and 3A4 induction in cryopreserved human hepatocytes. Evogliptin was found to be a substrate of P-gp, but not a substrate of BCRP, OAT1B1, OAT1B3, OAT1, OAT3, or OCT2, and not an inhibitor of any of these transporters.

Renal Impairment

In study cohorts classified using the MDRD eGFR, the geometric means ratio (90% CIs) of C_max and AUC_last were 1.52 (1.22-1.89) and 1.98 (1.59-2.46) for those with severe renal impairment versus healthy volunteers and 1.32 (1.08–1.61) and 1.8 (1.47–2.21) for those with moderate renal impairment versus healthy volunteers, respectively. In contrast, patients with mild renal impairment showed the PD parameters comparable to healthy volunteers; the corresponding geometric means ratio (90% CIs) of C_max and AUC_last were 1.04 (0.85-1.27) and 1.2 (0.98-1.47).

The toxicity of Evogliptin has been characterized in single and repeated oral dosing toxicity studies in mice, rats and dogs. Safety pharmacology studies and genotoxicity assessments have been also conducted. Carcinogenicity studies for 104 weeks in rats and dogs are on-going. In the acute toxicity study in rats, the lethal dose of Evogliptin was observed to be above 2,000 mg/kg. In the repeated dosing studies in mice, rats, and dogs, the no-observed-adverse-effect-level (NOAEL) was determined to be 300 mg/kg/day, 300 mg/kg/day, and 200 mg/kg/day, respectively.

In the study of bacterial reverse mutation, Evogliptin showed a negative response. Evogliptin did not induce chromosomal aberrations in cultured CHL cells. In vivo micronucleus test in bone marrow cells of ICR mice showed that Evogliptin did not induce an increased frequency of micronuclei in the bone marrow cells of ICR mice.

In safety pharmacology studies, it was confirmed that Evogliptin did not affect central nervous system and respiratory system after oral administration in rats, up to dose of 300 mg/kg. In a dog telemetry study, increase of heart rate, vomiting, and several changes of ECG parameter were observed at a high dose (300 mg/kg). But, there were no effects on blood pressure and body temperature even at the high dose (300 mg/kg). In hERG channel assay, an IC50 value of Evogliptin was approximately 143.4 μM. In consideration of C_max at 5 mg administration in humans, this IC50 value represents an enough safety margin over 10,000 times.

Pre-clinical studies revealed no carcinogenicity, mutagenicity and/or fertility impairment. Evogliptin showed no drug-related tumors in either sex of mice or rats upto the highest dose of 100 mg/kg/day (>25-fold or >80- fold higher exposure than in humans, respectively) for a period of two years.