title: CYP2D6 genotype affects age-related decline in flecainide clearance:  a population pharmacokinetic analysis.
abstract: OBJECTIVE
  To investigate the association between age-related decline in flecainide clearance and CYP2D6 genotype, we conducted a population pharmacokinetic analysis of flecainide using routine therapeutic drug monitoring data.
  
  
  METHODS
  Population pharmacokinetic analysis was performed on retrospective data from 163 genotyped patients treated with oral flecainide for supraventricular tachyarrhythmias. The CYP2D6 genotype was categorized as CYP2D6 homozygous extensive metabolizers (hom-EMs; n=57), heterozygous extensive metabolizers (het-EMs; n=79), and intermediate metabolizers and poor metabolizers (IMs/PMs; n=27).
  
  
  RESULTS
  Population pharmacokinetic analysis revealed that estimated glomerular filtration rate, body weight, female sex, and aging were important factors for estimating flecainide clearance. The metabolic clearance was decreased age dependently in a curvilinear fashion, where the lower clearance was observed in greater than 60 years for het-EMs and greater than 55 years for IMs/PMs. The reduction in metabolic clearance in elderly (70 years) patients compared with middle-aged (52 years) patients was different among the CYP2D6 genotype groups: 22.1 and 49.5% in CYP2D6 het-EMs and IMs/PMs, respectively, and no change in hom-EMs. A 11.4% reduction in estimated glomerular filtration rate in elderly patients compared with middle-aged patients corresponded to 6.1% decline in flecainide clearance. Overall, the age-related decline in flecainide clearance was 6.1% in hom-EMs, 16.3% in het-EMs, and 28.9% in IMs/PMs groups.
  
  
  CONCLUSIONS
  This study suggests that CYP2D6 genotype is a determinant factor of age-related decline in flecainide clearance.
authors.affiliation: Department of Pharmaceutical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Doki
authors.forename: Masato
authors.initials: M
authors.lastname: Homma
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kuga
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Aonuma
authors.forename: Yukinao
authors.initials: Y
authors.lastname: Kohda
mesh_terms: D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D016903:Drug Monitoring; D005260:Female; D005424:Flecainide / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005838:Genotype; D005919:Glomerular Filtration Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D012189:Retrospective Studies
chemical_list: D000889:Anti-Arrhythmia Agents; D019389:Cytochrome P-450 CYP2D6; D005424:Flecainide