¹Department of Medicine, Department of Clinical Laboratories, and Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, and Department of Clinical Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto.

Correspondence: Mitsushige Sugimoto, MD, First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192, Japan E-mail: mitsu@hama-med.ac.jp

^*This study was supported by a grant in aid (No. 99-2) from the Organization for Pharmaceutical Safety and Research, a Scientific Research grant from the YOKOYAMA Foundation for Clinical Pharmacology, and a grant in aid from the Center of Excellence from the Ministry of Education, Culture, Sports, Science and Technology, Tokyo, Japan.

Received 27 February 2004; Accepted 29 June 2004.

Abstract

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.