title: Pharmacokinetic and pharmacodynamic population modeling of orally administered rabeprazole in healthy Chinese volunteers by the NONMEM method.
abstract: The pharmacokinetic-pharmacodynamic (PK-PD) relationship of the proton pump inhibitor rabeprazole in healthy Chinese volunteers was characterized via a population approach. Healthy Chinese male volunteers were enrolled in the clinical trial. Subjects were divided into three groups by their CYP2C19 genotype. Serum concentrations of rabeprazole were determined using high performance liquid chromatography (HPLC). The intragastric pH values were monitored simultaneously. Data analysis was performed using nonlinear mixed-effects modeling as implemented in the NONMEM software package. The final PK-PD model incorporated a one-compartment PK model with one-order absorption from the gastroenteric trace, first-order elimination pathway with one fixed-effect genotype modeling, and a full sigmoidal Emax PD model (X +/- SE: E0 = 2.30 +/- 0.189; Emax = 7.32 +/- 0.662; EC50 = 51.3 +/- 2.142 ng/ml; Hill coefficient = 5.00 +/- 0.556). The time profiles for concentration and pH value, as well as the concentration-pH value relationship of rabeprazole in healthy Chinese volunteers were well described by the developed population PK-PD model.
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Zhi-Yang
authors.initials: ZY
authors.lastname: Chen
authors.forename: Hai-Tang
authors.initials: HT
authors.lastname: Xie
authors.forename: Qing-Shan
authors.initials: QS
authors.lastname: Zheng
authors.forename: Rui-Yuan
authors.initials: RY
authors.lastname: Sun
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000328:Adult; D000465:Algorithms; D000897:Anti-Ulcer Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001562:Benzimidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D065731:Cytochrome P-450 CYP2C19; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D017711:Nonlinear Dynamics; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D011153:Population; D064750:Rabeprazole; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D001562:Benzimidazoles; D064750:Rabeprazole; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole