title: Population pharmacokinetic analysis of letrozole in Japanese postmenopausal women.
abstract: OBJECTIVE
  Letrozole is an orally active aromatase inhibitor for the treatment of breast cancer. The objectives of this study were to examine the pharmacokinetic profile of letrozole in Japanese subjects and to identify factors that influence variability in the pharmacokinetics of letrozole using population pharmacokinetic (PPK) analysis.
  
  
  METHODS
  Twenty-five healthy postmenopausal Japanese women were enrolled in the study and received 2.5 mg letrozole once daily for 14 or 28 days. A PPK model was developed using NONMEM software. Age, body weight (WT), AST, ALT, total bilirubin, serum creatinine (CRE), and genotype of CYP2A6 were studied as covariates. Estrone, estrone sulfate, and estradiol in plasma were measured as pharmacodynamic markers.
  
  
  RESULTS
  CYP2A6 genotype, CRE, and AST were significant covariates for apparent systemic clearance (CL/F), and WT was a significant covariate for apparent distribution volume (Vd/F). Population mean estimates of CL/F and Vd/F in subjects without CYP2A6 mutation were 1.03 × (CRE/0.70)(-1.27) × (AST/17.5)(-0.793) L/h and 94.2 × (WT/51.1)(1.12) L respectively. CL/F in subjects possessing 1 and 2 CYP2A6 mutation alleles were 84.3% and 44.8% of the value in the subjects without mutation respectively. Estrogen levels fell to below detection limits in most subjects after letrozole administration. Three mild and transient adverse events (upper respiratory tract inflammation, arthralgia, and vomiting) were reported in the study.
  
  
  CONCLUSIONS
  CYP2A6 genotype largely influences CL/F of letrozole. Genetic polymorphism of CYP2A6 and body weight will be causes of ethnic difference in PK. However, dose adjustment is not necessary, because of the wide therapeutic range.
authors.affiliation: Translational Science Department, Novartis Pharma K.K., 4-17-30, Nishiazabu, Minato-ku, Tokyo 106-8616, Japan. hiromi.tanii@novartis.com
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tanii
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Shitara
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Horie
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D044466:Asian People; D001663:Bilirubin / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D065637:Cytochrome P-450 CYP2A6; D004958:Estradiol / Q000097:blood; D004970:Estrone / Q000031:analogs & derivatives / Q000097:blood; D005260:Female; D005838:Genotype; D006801:Humans; D000077289:Letrozole; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D017698:Postmenopause / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D004970:Estrone; D004958:Estradiol; D000077289:Letrozole; D003404:Creatinine; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; C017296:estrone sulfate; D001663:Bilirubin