Clinical Usefulness of Limited Sampling Strategies for Estimating AUC of Proton Pump Inhibitors

Abstract

Cytochrome P450 (CYP) 2C19 (CYP2C19) genotype is regarded as a useful tool to predict area under the blood concentration-time curve (AUC) of proton pump inhibitors (PPIs). In our results, however, CYP2C19 genotypes had no in‰uence on AUC of all PPIs during ‰uvoxamine treatment. Theseˆndings suggest that CYP2C19 genotyping is not always a good indicator for estimating AUC of PPIs. Limited sampling strategies (LSS) were developed to estimate AUC simply and accurately. It is important to minimize the number of blood samples because of patient's acceptance. This article reviewed the usefulness of LSS for estimating AUC of three PPIs (omeprazole: OPZ, lansoprazole: LPZ and rabeprazole: RPZ). The best prediction formulas in each PPI were AUC OPZ ＝9.24×C 6h ＋2638.03, AUC LPZ ＝12.32 ×C 6h ＋3276.09 and AUC RPZ ＝1.39×C 3h ＋7.17×C 6h ＋344.14, respectively. In order to optimize the sampling strategy of LPZ, we tried to establish LSS for LPZ using a time point within 3 hours through the property of pharmacokinetics of its enantiomers. The best prediction formula using the fewest sampling points (one point) was AUC racemic LPZ ＝6.5× C 3h of (R)-LPZ＋13.7×C 3h of (S)-LPZ-9917.3×G1-14387.2×G2＋7103.6 (G1: homozygous extensive metabolizer is 1 and the other genotypes are 0; G2: heterozygous extensive metabolizer is 1 and the other genotypes are 0). Those strategies, plasma concentration monitoring at one or two time-points, might be more suitable for AUC estimation than reference to CYP2C19 genotypes, particularly in the case of coadministration of CYP mediators.

Evaluation of Omeprazole Limited Sampling Strategies to Estimate Constitutive Cytochrome P450 2C19 Activity in Healthy Adults

“…This study was unable to develop an acceptable omeprazole LSS model to estimate CL/F with NCA. These results add to the conflicting literature that support 5,17,18 and refute 19 the suitability of an omeprazole LSS approach. Differences in sample size, selection of omeprazole phenotyping parameter, and method of model validation exist among studies that may explain these conflicting findings.…”

“…The selection of CL/F as a function of a partial AUC was done since omeprazole AUC currently lacks adequate validation, and using the AUC ratio of omeprazole to 5-hydroxyomeprazole has limited generalizability. Niioka reported three limited sampling models of plasma concentrations to estimate omeprazole AUC 5 . In a separate analysis of external data sets but using the same limited sampling models 5 , each model had bias and lacked precision 19 .…”

“…Niioka reported three limited sampling models of plasma concentrations to estimate omeprazole AUC 5 . In a separate analysis of external data sets but using the same limited sampling models 5 , each model had bias and lacked precision 19 . In another study, a three-time point limited sampling model accurately estimated the AUC ratio of omeprazole to 5-hydroxyomeprazole 4 , but was only applicable to Caucasian CYP2C19*1/*1 subjects.…”

“…Traditional LSS entailed randomizing subject data into training (n=56) and validation (n=114) sets. The selected time points were 0, 1, 2, 4, and/or 6-hours post dose since these were observed across all studies (Table 1, Supplemental Digital Content) and were evaluated in a previous study 5 . Linear regression equations to estimate CL/F as a function of partial AUCs 14,15 were derived from the training set.…”

“…Limited sampling strategy (LSS) is a validated method to estimate PK parameters from a reduced number of blood samples. Omeprazole LSS utilizing plasma concentrations and AUC ratios have been previously published 4,5 . However, study design limitations (i.e., small sample sizes) existed for previously reported studies (n=18 and 37) and complicate the ability to recommend such LSS models for general use.…”