Identification of the time-point which gives a plasma rabeprazole concentration that adequately reflects the area under the concentration-time curve

Objective: The purpose of this study is to evaluate whether a simple formula using limited blood samples can predict the area under the plasma rabeprazole concentration-time curve (AUC) in co-administration with CYP inhibitors. Methods: A randomized double-blind placebo-controlled crossover study design in three phases was conducted at intervals of 2 weeks. Twenty-one healthy Japanese volunteers, including three CYP2C19 genotype groups, took a single oral 20-mg dose of rabeprazole after three 6-day pretreatments, i.e., clarithromycin 800 mg/day, fluvoxamine 50 mg/day, and placebo. Prediction formulas of the AUC were derived from pharmacokinetics data of 21 subjects in three phases using multiple linear regression analysis. Ten blood samples were collected over 24 h to calculate AUC. Plasma concentrations of rabeprazole was measured by an HPLC-assay (l.l.q.=1 ng/ml). Results: The AUC was based on all the data sets (n=63). The linear regression using two points (C3 and C6) could predict AUC_0-∞ precisely, irrespective of CYP2C19 genotypes and CYP inhibitors (AUC_0-∞=1.39×C3+7.17×C6+344.14, r ²=0.825, p<0.001). Conclusion: The present study demonstrated that the AUC of rabeprazole can be estimated by the simple formula using two-point concentrations. This formula can be more accurate for the prediction of AUC estimation than that reflected by CYP2C19 genotypes without any determination, even if there are significant differences for the CYP2C19 genotypes. Therefore, this prediction formula might be useful to evaluate whether CYP2C19 genotypes really reflects the curative effect of rabeprazole.