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Pharmacodynamic effects: After single and multiple oral dosing with 50 mg and 100 mg of tegoprazan to healthy subjects, tegoprazan showed rapid and potent inhibitory effects on gastric acid secretion from the first dose. Intragastric pH above 4 was reached within 1 hour. The 24-hr pH 4 holding time ratio after single dosing with 50 mg and 100 mg of tegoprazan were 55.07% to 68.38%, respectively. After seven days if multiple dosing with 50 mg and 100 mg of tegoprazan, the 24-hr pH 4 holding time ratio were 58.35% and 66.55%, respectively.
Using AUC as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown.
After multiple oral dosing with 100 mg tegoprazan, the gastrin level was significantly increased compared to the baseline during treatment period. However, it was returned to baseline level in safety follow-up visit after the treatment period was over.
It has been reported that there is a potential risk of change in normal intestinal flora and proliferation of harmful bacteria such as Salmonella, Campylobacter, Clostridium difficile due to decrease in gastric acidity when taking acid suppressants. Treatment with tegoprazan also may lead to increased risk of gastrointestinal infections.
Clinical studies: Erosive Gastroesophageal Reflux Disease: A randomized, double-blind, active-controlled, comparative phase III study was conducted in 302 patients with erosive gastroesophageal reflux disease to evaluate K-CAB 50 mg, 100 mg or esomeprazole 40 mg for up to 8 weeks. The cumulative healing rate at week 8 was 98.91% (91 patients/92 patients), 98.90% (90 patients/91 patients), and 98.86% (87 patients/88 patients), respectively, in the K-CAB 50 mg, 100 mg and esomeprazole 40 mg treatment groups, demonstrating non-inferiority. (See Table 1.)
Click on icon to see table/diagram/imageNon-Erosive Gastroesophageal Reflux Disease: A randomized, double-blind, placebo-controlled, phase III study was conducted in 324 patients with non-erosive gastroesophageal reflux disease to evaluate K-CAB 50 mg, 100 mg or placebo for 4 weeks. The rate of patients with complete resolution of main symptoms, heartburn and reflux of gastric acid, at week 4 was 42.45% (45 patients/106 patients), 48.48% (48 patients/99 patients), 24.24% (24 patients/99 patients), respectively in treatment group of K-CAB 50 mg, 100 mg and placebo, demonstrating superiority (Table 2). (See Table 2.)
Click on icon to see table/diagram/imageGastric Ulcer: A randomized, double-blind, active-controlled, comparative phase III study was conducted in 306 patients with gastric ulcer to evaluate K-CAB 50 mg, 100 mg or lansoprazole 30 mg for up to 8 weeks. The cumulative healing rate at week 8 was 100.00% (88 patients/88 patients), 97.85% (91 patients/93 patients), and 100.00% (85 patients/85 patients), respectively, in the K-CAB 50 mg, 100 mg and 30 mg lansoprazole treatment groups, demonstrating non-inferiority. (See Table 3.)
Click on icon to see table/diagram/imageEradication of H. pylori concurrently given with appropriate antibiotic therapy treatment in patients with peptic ulcer and/or chronic atrophic gastritis: Two randomized, double-blind, active-controlled, comparative phase III studies were conducted in H. pylori positive patients to evaluate K-CAB 50 mg or lansoprazole 30 mg in combination with amoxicillin 1 g and clarithromycin 500 mg twice daily for 7 days. The H. pylori eradication rate was demonstrated the non-inferiority of K-CAB 50 mg-based triple therapy to lansoprazole 30 mg-based triple therapy (Table 4). (See Table 4.)
Click on icon to see table/diagram/imagePharmacokinetics: Absorption: Tmax of tegoprazan following single oral dose to healthy adults was ranged from 0.5 to 1.5 hours across the doses tested 50 ~ 400 mg. After single administration, the mean peak plasma concentration (Cmax) and mean exposure level (AUC) tended to increase dose portionally within the administration dose range. After 7 days of repeated administration, the mean peak plasma concentration of each dose group was similar or decreased in comparison with that of single administration.
Food effects on bioavailability were evaluated after administration of 200 mg of oral tegoprazan fasting and after meals to healthy adults. Although there was a tendency to delay the Tmax and decrease the Cmax after food intake, there was no significant difference on the AUClast and pharmacodynamic parameter (the maintenance time of intragastric acidity above pH 4).
Food effects on bioavailability were evaluated after administration of 50 mg of oral tegoprazan fasting, before meals or after meals to healthy adults. Although there was a tendency to delay the Tmax and decrease the Cmax after food intake, there was no significant difference on the AUClast and pharmacodynamic parameter (the maintenance time of intragastric acidity above pH 4).
Distribution: The proportion of in vitro non-protein-binding drug was 8.7 ~ 9.0% human in the concentration range of 1 ~ 10 μM.
Metabolism and Excretion: Tegoprazan is mainly metabolized by CYP3A4. The main metabolite is metabolite M1 (dealkylated metabolite).
After intravenous administration of tegoprazan to rats and dogs, amount of unchanged tegoprazan excreted in urine was less than 1%. After oral administration of [14C]-tegoprazan to rats, recovery of radioactivity at 168 hours (of dosing) were 93% and 97% in the female and male, respectively. 22% to 24% of the total radioactivity was excreted in urine, and 65% to 69% was eliminated in feces in both female and male rats. After oral administration to rats with biliary intubation, tegoprazan was excreted 41.4% in bile acid, 25.7% in urine and 28.4% in feces. And the total recovery of radioactivity was 97.7%. Less than 1% of unchanged tegoprazan was found 1% in bile acid and urine, 15% was in feces. 6% of metabolite M1 was found in feces.
Following the administration of tegoprazan to healthy male subjects, the plasma elimination half-life of unchanged tegoprazan and metabolite M1 were 4.1 hours and 22.8 hours, respectively. Urinary excretion rate of the unchanged tegoprazan was approximately 4.1% and the clearance was 1.1 L/hr. Urinary excretion rate of the major metabolite M1 was about 2.3% and the clearance was 0.5 L/hr.
Toxicology: Nonclinical safety data: Mutagenesis: Tegoprazan was negative in the bacterial reverse mutation test using Salmonella and E. coli. Tegoprazan was positive in the CHL cell chromosome aberration assay but negative in the in vivo micronucleus test using rat bone marrow cells not to induce micronucleus.
Carcinogenesis: In a 2-year carcinogenicity study in rats, gastrointestinal neuroendocrine tumor was observed in the male 15 mg/kg/day (about 4.8 times AUC of the recommended human dose) group and the female 6 mg/kg/day (about 6.8 times AUC of the recommended human dose).
Impairment of Fertility: No effects on fertility and early embryonic development were observed up to a high dose of 500 mg/kg/day. As a result of the embryo-fetal development studies, short supernumerary cervical ribs were observed with a higher incidence in rats. The NOAEL for maternal rats was determined to be 500 mg/kg/day, which was 369 times the AUC of the human recommended dose, and the NOEL for embryos and fetuses was determined to be 20 mg/kg/day, which was 15.6 times the AUC of the human recommended dose.
There were no effects on fetal development despite abortions and weight loss symptoms in the maximum dose (10 mg/kg/day) group of rabbit. The NOAEL for maternal rabbits was determined to be 5 mg/kg/day, which was 2 times the AUC of the human recommended dose, and the NOAEL for embryos and fetuses was determined to be 10 mg/kg/day, which was 4.8 times the AUC of the human recommended dose.
In a pre- and post-natal development study and maternal function study in rats, tegoprazan and metabolite M1 were shown to be excreted in breast milk. And the NOAEL was determined to be 20 mg/kg/day, which was 8 times the AUC of the human recommended dose on the basis of the decreased survival rate of the first filial rats at 60 mg/kg/day, the maximal dose.
