title: Association of CYP2C19 polymorphisms and lansoprazole-associated respiratory adverse effects in children.
abstract: OBJECTIVE
  To determine whether cytochrome P450 (CYP)2C19 haplotype associates with lansoprazole-associated adverse event frequency.
  
  
  METHODS
  Respiratory adverse events from a clinical trial of lansoprazole in children with asthma were analyzed for associations with extensive or poor metabolizer (PM) phenotype based on CYP2C19 haplotypes. Carriers of CYP2C19*2, *3, *8, or *9 alleles were PMs; carriers of 2 wild-type alleles were extensive metabolizers (EMs). Plasma concentrations of lansoprazole were determined in PM and EM phenotypes.
  
  
  RESULTS
  The frequency of upper respiratory infection among PMs (n = 45) was higher than that among EMs (n = 91), which in turn was higher than that in placebo subjects (n = 135; P = .0039). The frequency of sore throat (ST) was similarly distributed among EMs and PMs (P = .0015). The OR (95% CI) for upper respiratory infections in PMs was 2.46 (1.02-5.96) (P = .046); for EMs, the OR (95% CI) was 1.55 (0.86-2.79). The OR (95% CI) for ST in EMs and PMs was 2.94 (1.23-7.05, P = .016) vs 1.97 (1.09-3.55, P = .024), respectively. Mean ± SD plasma concentrations of lansoprazole were higher in PMs than in EMs: 207 ± 179 ng/mL vs 132 ± 141 ng/mL (P = .04).
  
  
  CONCLUSIONS
  Lansoprazole-associated upper respiratory infections and ST in children are related in part to CYP2C19 haplotype. Our data suggest that lansoprazole-associated adverse events in children may be mitigated by adjusting the conventional dose in PMs. Additional studies are required to replicate our findings.
authors.affiliation: Center for Pharmacogenomics and Translational Research, Nemours Children's Clinic, Jacksonville, FL, USA. jlima@nemours.org
authors.forename: John J
authors.initials: JJ
authors.lastname: Lima
authors.forename: Jason E
authors.initials: JE
authors.lastname: Lang
authors.forename: Edward B
authors.initials: EB
authors.lastname: Mougey
authors.forename: Kathryn B
authors.initials: KB
authors.lastname: Blake
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: Janet T
authors.initials: JT
authors.lastname: Holbrook
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wise
authors.forename: W G
authors.initials: WG
authors.lastname: Teague
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000293:Adolescent; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics; D001991:Bronchitis / Q000139:chemically induced / Q000235:genetics; D002648:Child; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D005819:Genetic Markers; D060005:Genotyping Techniques; D006239:Haplotypes; D006801:Humans; D064747:Lansoprazole; D016015:Logistic Models; D008297:Male; D016017:Odds Ratio; D010612:Pharyngitis / Q000139:chemically induced / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D054328:Proton Pump Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012141:Respiratory Tract Infections / Q000139:chemically induced* / Q000235:genetics
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D005819:Genetic Markers; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19
keywords: CYP; Cytochrome P450; EM; Extensive metabolizer; PM; PPI; Poor metabolizer; Proton pump inhibitor; SNP; ST; Single nucleotide polymorphism; Sore throat; URI; Upper respiratory tract infection; WT; Wild type