title: Comparison of pharmacokinetic variability of fesoterodine vs. tolterodine extended release in cytochrome P450 2D6 extensive and poor metabolizers.
abstract: BACKGROUND
  Tolterodine and 5-hydroxymethyl tolterodine (5-HMT) are equipotent active moieties of tolterodine; 5-HMT is the singular active moiety of fesoterodine. The formation of 5-HMT from tolterodine occurs via CYP2D6, and some subjects are poor metabolizers CYP2D6. On the other hand, the formation of 5-HMT from fesoterodine occurs via ubiquitous esterases. Cross-study comparisons of data from phase 1 studies suggest that active moiety exposures are considerably more variable following tolterodine extended release vs. fesoterodine.
  
  
  CONCLUSIONS
  This head-to-head study confirmed the findings of reduced pharmacokinetic variability of fesoterodine and further delineates that tolterodine, and not 5-HMT, was the principal source of variability after administration of tolterodine extended release. The data suggest that fesoterodine delivers 5-HMT consistently, regardless of CYP2D6 status, with up to 40% higher bioavailability compared with tolterodine.
  
  
  OBJECTIVE
  Tolterodine and 5-hydroxymethyl tolterodine (5-HMT) are equipotent active moieties of tolterodine; 5-HMT is the singular active moiety of fesoterodine. Formation of 5-HMT from fesoterodine and tolterodine occurs via esterases and CYP2D6 respectively. This randomized, crossover, open-label, multiple-dose study in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) compared the pharmacokinetics of fesoterodine vs. tolterodine extended release (ER).
  
  
  METHODS
  Subjects received fesoterodine and tolterodine ER with a ≥3-day washout period. Treatment comprised 4-mg once daily doses for 5 days escalated to 8-mg once daily for 5 days. Pharmacokinetics of active moieties were compared by drug, dose and genotype.
  
  
  RESULTS
  Active moiety exposures following fesoterodine and tolterodine ER increased proportional to dose in EMs and PMs. In EMs only, coefficients of variation for AUC and C(max) following fesoterodine (up to 46% and 48% respectively) were lower than those following tolterodine ER (up to 87% and 87% respectively). Following fesoterodine and tolterodine ER administration, active moiety exposures ranged up to sevenfold and 40-fold respectively. Mean urinary excretion of 5-HMT following fesoterodine 4 and 8 mg, respectively, was 0.44 and 0.89 mg in EMs and 0.60 and 1.32 mg in PMs. Following tolterodine ER 4 and 8 mg, it was 0.38 and 0.71 mg respectively (EMs only). Renal clearance was similar regardless of administered drug, dose or genotype.
  
  
  CONCLUSIONS
  Tolterodine, not 5-HMT, was the principal source of variability after tolterodine ER administration. Fesoterodine delivers 5-HMT with less variability than tolterodine, regardless of CYP2D6 status, with up to 40% higher bioavailability. The pharmacokinetics of fesoterodine were considerably less variable than TER.
authors.affiliation: Pfizer Inc., New York, NY, USA Pfizer Global Research and Development, Sandwich, Kent, UK. bimal.k.malhotra@pfizer.com
authors.forename: Bimal
authors.initials: B
authors.lastname: Malhotra
authors.forename: Edress
authors.initials: E
authors.lastname: Darsey
authors.forename: Penelope
authors.initials: P
authors.lastname: Crownover
authors.forename: Juanzhi
authors.initials: J
authors.lastname: Fang
authors.forename: Paul
authors.initials: P
authors.lastname: Glue
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D001682:Biological Availability; D003408:Cresols / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010665:Phenylpropanolamine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000068737:Tolterodine Tartrate
chemical_list: C109909:5-hydroxymethyl tolterodine; D001559:Benzhydryl Compounds; D003408:Cresols; D018727:Muscarinic Antagonists; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; C526675:fesoterodine; D019389:Cytochrome P-450 CYP2D6