Pharmacokinetic and Pharmacodynamic Evaluation of a Novel Proton Pump Inhibitor, YH1885, in Healthy Volunteers

Abstract

To evaluate the pharmacokinetic and pharmacodynamic characteristics of YH1885, a novel proton pump inhibitor, a single-blind, randomized, placebo-controlled, dose-rising, parallel-group study was conducted in 46 healthy volunteers. The volunteers were randomly allocated to single dose groups of 60 mg, 100 mg, 150 mg, 200 mg, and 300 mg (6 subjects per dose, including 2 placebos) or to multiple-dose groups of 150 mg and 300 mg (once-daily dosing for 7 days; 8 subjects per dose, including 2 placebos). The multiple-dose study was conducted separately after the single-dose study. YH1885 was administered orally after overnight fasting. Serial blood samples, urine samples, and pharmacodynamic measurements were taken. Drug concentrations in plasma and urine were determined by liquid chromatography/mass spectrometry (LC/MS). Pharmacodynamic changes were evaluated by ambulatory intragastric pH monitoring and by serial measurements of serum gastrin concentrations. Assessments of safety and tolerability also were made. Plasma concentrations of YH1885 reached peak levels 1.3 to 2.5 hours after single-dose administration and then declined monoexponentially with a terminal half-life (t(1/2)) of 2.2 to 2.4 hours in dosage groups up to 200 mg in the single-dose study. YH1885 showed linear pharmacokinetic characteristics, and little accumulation occurred after multiple administrations. The parent drug was not detected in urine. Dose-related pharmacological effects were obvious for dose groups of 150 mg and higher in the single-dose study. The mean intragastric pH and the percentage of time at pH>4 were significantly increased. The onset of drug effect was rapid, and maximal effects were observed on the first day of administration during multiple dosing. Serum gastrin levels also showed rapid increases during dosing but with a weak dose-effect relationship. Neither serious nor dose-limiting adverse effects were observed. YH1885 was found to be safe and well tolerated and effectively inhibited acid secretion with dose-dependent increases in intragastric pH. The acid-suppressing efficacy of YH1885 needs to be further evaluated in patients with gastric acid-related diseases.

The gastric HK-ATPase: structure, function, and inhibition

“…Revaprazan is a pyrimidine derivative, N-(4-fluorophenyl)-4,5-dimethyl-6-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidin-2-amine hydrochloride. Revaprazan demonstrated dose-dependent inhibition and reached maximal effect at day 1 during the multiple-dose study, which is different from PPIs [17,73]. Revaprazan is now clinically used in the Far East.…”

The Novel Acid Pump Antagonists for Anti-secretory Actions with Their Peculiar Applications Beyond Acid Suppression

“…Revaprazan (Revanex ® ), 5,6-dimethyl-2-(4-fluorophenylamino)-4- (1-methyl-1,2,3,4,-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride, is a novel APA that is currently approved by the Korea Food and Drug Administration (KFDA) as new drug for the treatment of gastric diseases including peptic ulcer disease (Fig. 4A and B) [28,29]. This APA presents a reversible mode of action against H + / K + -ATPase, which is distinct from that of PPIs known for an irreversible inhibition (Fig.…”

The Potential Inhibitory Effect of Revaprazan, an Acid Pump Antagonist, on Anticoagulation with Warfarin

“…Revaprazan is the first APAs (Yu et al 2004) featuring suppression of acid secretion and protection of gastric membrane, and displayed a quick and powerful suppression of gastric acid secretion in clinical tests. This is especially apparent when observing the pH change in the stomach over a 24 hour period.…”

“…This is especially apparent when observing the pH change in the stomach over a 24 hour period. Its pharmacological action begins very rapidly compared to existing irreversible PPIs (Yu et al 2004). In clinical tests, it was effective with a once daily dose in maintaining gastric pH at 3 and higher for 24 hours in the treatment of peptic ulcer and its safety and effectiveness were proven by a phase II clinical study.…”

“…While proton pump inhibitors (PPIs) reduce acid secretion by irreversibly suppressing H + /K + -ATPase enzyme, the last step in gastric acid secretion, revaprazan reversibly inhibits the exchange of H + -ion by competitively adhering to the K + -ion binding area in acid pump, thereby reducing acid secretion without hypergastrinemia. With these pharmacological differences, revaprazan has advantages such as rapid onset of action independent of gastric acid secretion as well as ability to control physiological gastric acid secretion (Yu et al 2004). Owing to these advantages, Revaprazan is being prescribed more frequently in clinical settings as a substitute for PPIs in Asian countries.…”