Different dosage regimens of rabeprazole for nocturnal gastric acid inhibition in relation to cytochrome P450 2C19 genotype status

• Published in: Clinical pharmacology and therapeutics Vol. 76; no. 4; p. 290
• Main Authors: Sugimoto, Mitsushige, Furuta, Takahisa, Shirai, Naohito, Kajimura, Masayoshi, Hishida, Akira, Sakurai, Masaharu, Ohashi, Kyoichi, Ishizaki, Takashi
• Format: Journal Article
• Language: English
• Published: United States 01.10.2004
• Subjects: 2-Pyridinylmethylsulfinylbenzimidazoles; Administration, Oral; Anti-Ulcer Agents - administration & dosage; Anti-Ulcer Agents - pharmacokinetics; Anti-Ulcer Agents - pharmacology; Area Under Curve; Aryl Hydrocarbon Hydroxylases - genetics; Benzimidazoles - administration & dosage; Benzimidazoles - blood; Benzimidazoles - pharmacokinetics; Benzimidazoles - pharmacology; Cytochrome P-450 CYP2C19; Drug Administration Schedule; Female; Gastric Acid - secretion; Genotype; Humans; Male; Mixed Function Oxygenases - genetics; Omeprazole - analogs & derivatives; Polymorphism, Genetic - physiology; Proton-Translocating ATPases - antagonists & inhibitors; Rabeprazole; Stomach - drug effects; Stomach - metabolism
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/j.clpt.2004.06.008

For the treatment of gastroesophageal reflux disease, intragastric pH should be lower than 4.0 for no more than 4 hours a day (<16.7%). We aimed to develop optimal dosage regimens for rabeprazole to control nocturnal acidity in relation to cytochrome P450 (CYP) 2C19 genotypes. Fifteen Helicobacter pylori -negative volunteers, comprising 5 homozygous extensive metabolizers (EMs), 6 heterozygous EMs, and 4 poor metabolizers (PMs) of CYP2C19, took placebo and rabeprazole, at a dose of 20 or 40 mg once daily (at 10 pm ) for 8 days. Plasma rabeprazole concentrations and 24-hour intragastric pH were determined on days 7 and 8, respectively. Because the nocturnal intragastric pH was lower than 4.0 for more than 16.7% of the time with once-daily regimens in homozygous EMs and heterozygous EMs, they were administered 20 mg rabeprazole twice daily (8 am and 10 pm ) or 10 mg rabeprazole 4 times daily (8 am , 12:30 pm , 6 pm , and 10 pm ). With 40 mg rabeprazole once daily, the median percent time with nocturnal pH lower than 4.0 was less than 16.7% in PMs (9.5% [range, 3.0%-31.1%]) but not in homozygous EMs (45.3% [range, 29.0%-52.2%]) ( P = .043) and heterozygous EMs (41.3% [range, 33.0%-59.0%]) ( P = .043). The mean plasma rabeprazole concentrations differed among the different CYP2C19 genotype groups. With 20 mg rabeprazole twice daily and 10 mg rabeprazole 4 times daily, the median percent times with nocturnal pH lower than 4.0 were 5.0% (range, 0.0%-42.0%) and 1.0% (range, 5.0%-7.1%) in heterozygous EMs and 62.0% (range, 10.8%-68.3%) and 14.7% (range, 0.0%-41.7%) in homozygous EMs, respectively, and plasma concentrations were sustained longer than with the once-daily regimens. We propose that rabeprazole dosage regimens for sufficient acid inhibition are 20 mg once daily for PMs, 20 mg twice daily for heterozygous EMs, and 10 mg 4 times daily for homozygous EMs or heterozygous EMs.