Different dosage regimens of rabeprazole for nocturnal gastric acid inhibition in relation to cytochrome P450 2C19 genotype status.
Author(s): Sugimoto M, Furuta T, Shirai N, Kajimura M, Hishida A, Sakurai M, Ohashi K, Ishizaki T
Affiliation(s): First Department of Medicine, Hamamatsu University School of Medicine, Japan. mitsu@hama-med.ac.jp
Publication date & source: 2004-10, Clin Pharmacol Ther., 76(4):290-301.
Publication type: Clinical Trial; Randomized Controlled Trial
OBJECTIVE: 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. METHODS: 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 ). RESULTS: 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. CONCLUSIONS: 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.
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