ABSTRACT
PURPOSE: 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.
Subject(s)
Anti-Ulcer Agents/pharmacokinetics , Aryl Hydrocarbon Hydroxylases/metabolism , Cytochrome P-450 CYP3A/metabolism , Omeprazole/pharmacokinetics , 2-Pyridinylmethylsulfinylbenzimidazoles/blood , Adolescent , Adult , Anti-Ulcer Agents/blood , Area Under Curve , Aryl Hydrocarbon Hydroxylases/genetics , Asian People/genetics , Cytochrome P-450 CYP2C19 , Female , Genotype , Humans , Male , Models, Biological , Omeprazole/analogs & derivatives , Omeprazole/blood , Phenotype , White People/genetics , Young AdultABSTRACT
We describe a pediatric patient with acute leukemia who developed an uncommon but significant metabolic consequence of pegaspargase therapy-severe hypertriglyceridemia (hyperTG). We also relate our experience with continuous insulin infusion treatment for pegaspargase-induced hyperTG. This treatment approach led to a decrease in triglycerides from 4640 mg/dL on admission to 522 mg/dL at discharge 9 days later. Genetic testing revealed that our patient was an apolipoprotein E 3/4 heterozygote. Our review of the literature suggests that apolipoprotein E polymorphism may influence the development of hyperlipidemia in acute lymphoblastic leukemia patients receiving asparaginase therapy and may identify patients at high risk for developing asparaginase-induced hyperTG.
