title: Pharmacokinetic and Pharmacodynamic Modeling Analysis of Intravenous Esomeprazole in Healthy Volunteers.
abstract: Esomeprazole is one of the most commonly used drugs to treat gastroesophageal reflux disease and peptic ulcers, but the quantitative relationships among the pharmacokinetics (PK), pharmacodynamics (PD), and pharmacogenomics (PG) of the drug are not fully understood in special patient populations. A clinical PK/PD/PG study of intravenous (IV) esomeprazole in 5 dosing regimens was conducted in 20 healthy Chinese volunteers, who were categorized into Helicobacter pylori (HP)-negative and HP-positive subgroups. Plasma esomeprazole concentration and intragastric H(+) concentration were monitored for 24 hours postdosing. Population PK (PopPK) models were tested based on elimination characteristics and other data. For a single-dose IV esomeprazole regimen, a 2-compartment model with nonlinear elimination characteristics fitted the PK data well. The elimination of esomeprazole was found to be significantly linked to CYP2C19 genotype by 11% to 29%. A mechanism-based PD model was first tested to mimic the irreversible inhibition of H(+) /K(+) -ATPase by esomeprazole using a cell-killing mechanism and models of gastric H(+) secretion that included the effects of an asymmetric circadian rhythm and food effects. Results from this PD model showed that the turnover rate of H(+) /K(+) -ATPase was significantly different between HP-negative and HP-positive subgroups. In conclusion, the PopPK model quantitatively identified the effects of the CYP2C19 genotype on esomeprazole elimination in healthy subjects for the first time. In addition, the effects of HP status on drug effect, H(+) /K(+) -ATPase turnover, and circadian rhythm amplitude were preliminarily explored using a mechanism-based PD model.
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Dongyang
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Jiang
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Péter
authors.initials: P
authors.lastname: Nagy
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Shen
authors.affiliation: Department of Gastroenterology, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Jiaming
authors.initials: J
authors.lastname: Qian
authors.affiliation: Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Hu
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000897:Anti-Ulcer Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D064098:Esomeprazole / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D064368:Healthy Volunteers; D016481:Helicobacter Infections / Q000188:drug therapy / Q000378:metabolism; D016480:Helicobacter pylori / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D055815:Young Adult
chemical_list: D000897:Anti-Ulcer Agents; D064098:Esomeprazole
keywords: CYP2C19 polymorphism; Helicobacter pylori status; esomeprazole; healthy Chinese volunteers; mechanism-based pharmacodynamic model; population pharmacokinetics