Omeprazole limited sampling strategies to predict area under the concentration–time curve ratios: implications for cytochrome P450 2C19 and 3A phenotyping

Abstract

A LSS model to predict AUC(OPZ)/AUC(5OH), and thus CYP2C19 activity, was generated for Caucasian CYP2C19*1/*1 subjects. However, additional model validation is needed prior to general use. LSS models to predict AUC(OPZ)/AUC(SUL), and thus CYP3A activity, were not possible, even upon stratification by CYP2C19 genotype and ethnicity.

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

“…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. To the best of our knowledge, this is the first LSS study to utilize an omeprazole CL/F as a function of a partial AUC to estimate CYP2C19 activity.…”

“…In other studies, model selection and model validation were primarily determined from the highest r 2 or correlation coefficient ( r ) 5,17 . Selecting a limited sampling model based on the highest r 2 or r may not be correct 4 since neither the r 2 norr r are measures of predictive performance 20 .…”

“…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.…”

Effects of vercirnon on the activity of CYP3A4, CYP2C19 and CYP2C8 enzymes and BCRP and OATP1B1 transporters using probe substrates

“…The primary endpoint for all probe substrates (except omeprazole) was the ratio of AUC 0–∞ for each of the probe substrates when administered with and without concomitant vercirnon. Due to the high inter- and intra-subject variability associated with omeprazole PK [12], its metabolite (5-OH-omeprazole) was also quantified in plasma and the ratio of omeprazole metabolite to parent was calculated to normalise for the variability associated with the absorption and metabolism of omeprazole. The statistical endpoint for omeprazole was calculated from the AUC 0–∞ ratio of metabolite:parent, both with and without concomitant vercirnon.…”

Limited Sampling Strategy for the Prediction of Area Under the Curve (AUC) of Statins: Reliability of a Single Time Point for AUC Prediction for Pravastatin and Simvastatin

“…In this context, it is critical to establish exposure to statins using sparse samples with reasonable accuracy since statins can also lead to several side effects including myopathy and life threatening rhabdomyolysis. The use of limited sampling strategy protocols have been applied to several drug classes to predict exposure values with reasonable accuracy to aid in decision making for dosing recommendations (increase or decrease) and also for drug switches, if deemed necessary [15][16][17]. In this context, TDM may help to gauge the need and dose(s) of other agents to be co-administered that may interfere in the metabolic pathways of statins or vice-versa.…”