title: Lansoprazole Is Associated with Worsening Asthma Control in Children with the CYP2C19 Poor Metabolizer Phenotype.
abstract: BACKGROUND
  Gastric acid blockade in children with asymptomatic acid reflux has not improved asthma control in published studies. There is substantial population variability regarding metabolism of and response to proton pump inhibitors based on metabolizer phenotype. How metabolizer phenotype affects asthma responses to acid blockage is not known.
  
  
  OBJECTIVE
  To determine how metabolizer phenotype based on genetic analysis of CYP2C19 affects asthma control among children treated with a proton pump inhibitor.
  
  
  METHODS
  Asthma control as measured by the Asthma Control Questionnaire (ACQ) and other questionnaires from a 6-month clinical trial of lansoprazole in children with asthma was analyzed for associations with surrogates of lansoprazole exposure (based on treatment assignment and metabolizer phenotype). Groups included placebo-treated children; lansoprazole-treated extensive metabolizers (EMs); and lansoprazole-treated poor metabolizers (PMs). Metabolizer phenotypes were based on CYP2C19 haplotypes. Carriers of the CYP2C19*2, *3, *8, *9, or *10 allele were PMs; carriers of two wild-type alleles were extensive metabolizers (EMs).
  
  
  RESULTS
  Asthma control through most of the treatment period was unaffected by lansoprazole exposure or metabolizer phenotype. At 6 months, PMs displayed significantly worsened asthma control compared with EMs (+0.16 vs. -0.13; P = 0.02) and placebo-treated children (+0.16 vs. -0.23; P < 0.01). Differences in asthma control were not associated with changes in gastroesophageal reflux symptoms. Recent upper respiratory infection worsened asthma control, and this upper respiratory infection effect may be more pronounced among lansoprazole-treated PMs.
  
  
  CONCLUSIONS
  Children with the PM phenotype developed worse asthma control after 6 months of lansoprazole treatment for poorly controlled asthma. Increased exposure to proton pump inhibitor may worsen asthma control by altering responses to respiratory infections. Clinical trial registered with www.clinicaltrials.gov (NCT00604851).
authors.affiliation: 1 Division of Pulmonary and Sleep Medicine, Nemours Children's Hospital/Nemours Research Institute, Orlando and.|2 Center for Pharmacogenomics and Translational Research, Nemours Children's Clinic, Jacksonville, Florida.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Lang
authors.affiliation: 3 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health and.
authors.forename: Janet T
authors.initials: JT
authors.lastname: Holbrook
authors.affiliation: 2 Center for Pharmacogenomics and Translational Research, Nemours Children's Clinic, Jacksonville, Florida.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Mougey
authors.affiliation: 3 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health and.
authors.forename: Christine Y
authors.initials: CY
authors.lastname: Wei
authors.affiliation: 4 Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wise
authors.affiliation: 5 University of Virginia School of Medicine, Charlottesville, Virginia.
authors.forename: W Gerald
authors.initials: WG
authors.lastname: Teague
authors.affiliation: 2 Center for Pharmacogenomics and Translational Research, Nemours Children's Clinic, Jacksonville, Florida.
authors.forename: John J
authors.initials: JJ
authors.lastname: Lima
mesh_terms: D000293:Adolescent; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D002648:Child; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D016903:Drug Monitoring; D005260:Female; D005764:Gastroesophageal Reflux / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D064747:Lansoprazole / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D062072:Patient Acuity; D010641:Phenotype; D011110:Polymorphism, Genetic; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D012141:Respiratory Tract Infections / Q000150:complications*; D013223:Statistics as Topic; D016896:Treatment Outcome
chemical_list: D005938:Glucocorticoids; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19
keywords: child; lansoprazole; phenotype; polymorphism (genetics)
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