title: CYP2C19-guided design of a proton pump inhibitor dose regimen to avoid the need for pharmacogenetic individualization in H. pylori eradication.
abstract: OBJECTIVE
  It has been demonstrated that genetic variation in CYP2C19 has a significant influence upon H. pylori eradication rates. We have determined a dosage regimen of lansoprazole that will provide EMs with exposure approximately equivalent to that obtained by PMs treated with standard doses and determined the exposure that a PM would experience if they were to be treated with this 'EM optimised' lansoprazole dose.
  
  
  METHODS
  Non-compartmental pharmacokinetic parameters (AUC, C(max), t(max)) for CYP2C19 genotypes were obtained from the literature. Primary pharmacokinetic parameters (CL, Vd, ka) for 200 virtual patients were calculated from the weighted non-compartmental variables and used to simulate a 7 day treatment course of twice daily lansoprazole, at standard and optimised doses for 1,000 patients.
  
  
  RESULTS
  The administration of 180 mg twice daily to CYP2C19 EMs results in approximately equivalent exposure to lansoprazole as the administration of standard 30 mg twice daily doses to PMs. Administration of this six-fold dose increase to EMs is predicted to result in only a 2.5-fold increase in C(max) when compared with PMs receiving the standard 30 mg dose.
  
  
  CONCLUSIONS
  We present a potential lansoprazole dosing regimen that should result in improved H. pylori eradication within CYP2C19 EMs and may not require individualization. Whilst the optimised dose represents a significant increase, it is below that reported in the chronic management of Zollinger-Ellison syndrome. On the basis that treatment is of limited duration and lansoprazole is generally well tolerated, such an approach warrants further in vivo evaluation to confirm drug exposure, efficacy and tolerability.
authors.affiliation: Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia. michael.ward@unisa.edu.au.au
authors.forename: Michael B
authors.initials: MB
authors.lastname: Ward
authors.forename: David J R
authors.initials: DJ
authors.lastname: Foster
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D004305:Dose-Response Relationship, Drug; D016481:Helicobacter Infections / Q000188:drug therapy*; D016480:Helicobacter pylori / Q000187:drug effects / Q000302:isolation & purification; D006801:Humans; D064747:Lansoprazole; D008954:Models, Biological; D010597:Pharmacogenetics; D054328:Proton Pump Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014018:Tissue Distribution; D015043:Zollinger-Ellison Syndrome / Q000188:drug therapy
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19