Pharmacokinetics and Pharmacodynamics of Azeloprazole Sodium, a Novel Proton Pump Inhibitor, in Healthy Japanese Volunteers

The pharmacokinetics (PK) and pharmacodynamics (PD) of proton pump inhibitors differ among cytochrome P450 (CYP) 2C19 genotypes. Therefore, we developed azeloprazole sodium (Z‐215), a novel proton pump inhibitor, whose metabolism is not affected by CYP2C19 activity in vitro. However, the PK and PD o...

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Bibliographic Details
Published in:Journal of clinical pharmacology 2018-04, Vol.58 (4), p.425-433
Main Authors: Toda, Ryoko, Shiramoto, Masanari, Komai, Emi, Yoshii, Kazuyoshi, Hirayama, Masamichi, Kawabata, Yoshihiro
Format: Article
Language:English
Subjects:
Adult
Anti-Ulcer Agents - blood
Anti-Ulcer Agents - pharmacology
Area Under Curve
Asian Continental Ancestry Group - genetics
Benzimidazoles - blood
Benzimidazoles - pharmacology
Cross-Over Studies
Cytochrome P-450 CYP2C19 - genetics
Cytochrome P450
Gastric Acidity Determination
Gastric Juice - chemistry
Gastroesophageal reflux
gastroesophageal reflux disease
Genotype
Genotypes
Healthy Volunteers
Humans
Hydrogen-Ion Concentration
intragastric pH
intragastric pH ≥ 4 holding time ratio
Male
Metabolism
pH effects
Pharmacodynamics
pharmacogenetics
Pharmacokinetics
Plasma
Proton pump inhibitors
Proton Pump Inhibitors - blood
Proton Pump Inhibitors - pharmacology
Protons
Sodium
Sulfoxides - blood
Sulfoxides - pharmacology
Young Adult
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Summary:The pharmacokinetics (PK) and pharmacodynamics (PD) of proton pump inhibitors differ among cytochrome P450 (CYP) 2C19 genotypes. Therefore, we developed azeloprazole sodium (Z‐215), a novel proton pump inhibitor, whose metabolism is not affected by CYP2C19 activity in vitro. However, the PK and PD of azeloprazole sodium have not been evaluated in Japanese subjects. We conducted an open‐label, crossover study in healthy Japanese male volunteers to evaluate the plasma concentration and intragastric pH with respect to CYP2C19 genotype after repeated administration of 10, 20, and 40 mg azeloprazole sodium and 10 and 20 mg rabeprazole sodium (rabeprazole). The plasma concentration profile of azeloprazole sodium was similar among genotypes, whereas that of rabeprazole differed. The 24‐hour intragastric pH ≥ 4 holding time ratio (pH ≥ 4 HTR) of azeloprazole sodium was similar among genotypes. The pH ≥ 4 HTR was 52.5%–60.3%, 55.1%–65.8%, and 69.4%–77.1% after administration of 10, 20, and 40 mg azeloprazole sodium, respectively, and 59.2%–72.3% and 64.4%–91.2% after administration of 10 and 20 mg rabeprazole, respectively, on the fifth day of dosing. The maximum plasma concentration (Cmax), area under the plasma concentration‐time curve (AUC), and pH ≥ 4 HTR of azeloprazole sodium were proportional to dose. The Cmax, AUC, and pH ≥ 4 HTR on day 5 were slightly higher following administration of 20 mg azeloprazole sodium before comparison with after a meal. No serious adverse events were observed. These results suggest that azeloprazole sodium is useful for treating gastroesophageal reflux disease in all CYP2C19 genotypes.
ISSN:0091-2700
1552-4604
DOI:10.1002/jcph.1038