Omeprazole limited sampling strategies to predict area under the concentration-time curve ratios: implications for cytochrome P450 2C19 and 3A phenotyping.
OBJECTIVE
To develop a limited sampling strategy (LSS) to predict area under the concentration-time curve (AUC) ratios of omeprazole (AUC(OPZ)) to its metabolites 5-hydroxyomeprazole (AUC(5OH)) and omeprazole sulfone (AUC(SUL)) as phenotyping parameters for cytochrome P450 (CYP) 2C19 and 3A.


METHODS
Data were obtained from 37 (4 women) Caucasian, Chinese, and Korean healthy adults from three published studies. The AUC(OPZ), AUC(5OH), and AUC(SUL) were calculated via noncompartmental analysis. Observed AUC(OPZ, OBS)/AUC(5OH, OBS) and AUC(OPZ, OBS)/AUC(SUL, OBS) were determined. Plasma concentrations of omeprazole, 5-hydroxyomeprazole, and omeprazole sulfone at 1, 1.5, 2, 3, 4, 6, and 8 h post-dose were used to generate limited sampling strategy (LSS) models to predict AUC(OPZ,PRE)/AUC(5OH,PRE) and AUC(OPZ,PRE/)AUC(SUL,PRE). Bias and precision were assessed via percentage mean prediction error (%MPE) and percentage mean absolute error (%MAE), with acceptable limits being <15%.


RESULTS
For CYP2C19, the AUC(OPZ,OBS)/AUC(5OH,OBS) was [mean ± standard deviation (SD)] 2.10 ± 1.63. Five LSS models of AUC(OPZ,PRE)/AUC(5OH,PRE) were generated, but none met the bias or precision criteria. Upon stratification by CYP2C19 genotype and ethnicity, a three-timepoint (at 1, 2, and 4 h) LSS model accurately predicted AUC(OPZ)/AUC(5OH) in Caucasian CYP2C19*1/*1 subjects. For CYP3A, AUC(OPZ,OBS)/AUC(SUL,OBS) (mean ± SD) was 1.79 ± 0.67. All LSS models had unacceptable %MAE, even when stratified by CYP2C19 genotype and ethnicity.


CONCLUSIONS
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.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego (UCSD), 9500 Gilman Drive, MC 0714, La Jolla, CA 92093-0714, USA.
Eileen B
EB
Lawson
Jerry C
JC
Wu
R Michael
RM
Baldwin
Magnus
M
Ingelman-Sundberg
Staffan
S
Rosenborg
Dong-Seok
DS
Yim
Ophelia Q P
OQ
Yin
Edmund V
EV
Capparelli
Joseph D
JD
Ma
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000097:blood; D000293:Adolescent; D000328:Adult; D000897:Anti-Ulcer Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D044466:Asian People / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008954:Models, Biological; D009853:Omeprazole / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D010641:Phenotype; D044465:White People / Q000235:genetics; D055815:Young Adult
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; C040450:omeprazole sulfone; C049963:5-hydroxymethylomeprazole; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C104464:CYP3A protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D009853:Omeprazole