title: Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism: a multicenter study.
abstract: OBJECTIVE
  We examined the feasibility of using CYP2D6 genotyping to determine optimal tamoxifen dose and investigated whether the key active tamoxifen metabolite, endoxifen, could be increased by genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism.
  
  
  METHODS
  One hundred nineteen patients on tamoxifen 20 mg daily ≥ 4 months and not on any strong CYP2D6 inhibiting medications were assayed for CYP2D6 genotype and plasma tamoxifen metabolite concentrations. Patients found to be CYP2D6 extensive metabolizers (EM) remained on 20 mg and those found to be intermediate (IM) or poor (PM) metabolizers were increased to 40 mg daily. Eighty-nine evaluable patients had tamoxifen metabolite measurements repeated 4 months later.
  
  
  RESULTS
  As expected, the median baseline endoxifen concentration was higher in EM (34.3 ng/mL) compared with either IM (18.5 ng/mL; P = .0045) or PM (4.2 ng/mL; P < .001). When the dose was increased from 20 mg to 40 mg in IM and PM patients, the endoxifen concentration rose significantly; in IM there was a median intrapatient change from baseline of +7.6 ng/mL (-0.6 to 23.9; P < .001), and in PM there was a change of +6.1 ng/mL (2.6 to 12.5; P = .020). After the dose increase, there was no longer a significant difference in endoxifen concentrations between EM and IM patients (P = .84); however, the PM endoxifen concentration was still significantly lower.
  
  
  CONCLUSIONS
  This study demonstrates the feasibility of genotype-driven tamoxifen dosing and demonstrates that doubling the tamoxifen dose can increase endoxifen concentrations in IM and PM patients.
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. wirvin@med.unc.edu
authors.forename: William J
authors.initials: WJ
authors.lastname: Irvin
authors.forename: Christine M
authors.initials: CM
authors.lastname: Walko
authors.forename: Karen E
authors.initials: KE
authors.lastname: Weck
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Ibrahim
authors.forename: Wing K
authors.initials: WK
authors.lastname: Chiu
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
authors.forename: Susan G
authors.initials: SG
authors.lastname: Moore
authors.forename: Oludamilola A
authors.initials: OA
authors.lastname: Olajide
authors.forename: Mark L
authors.initials: ML
authors.lastname: Graham
authors.forename: Sean T
authors.initials: ST
authors.lastname: Canale
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Raab
authors.forename: Steven W
authors.initials: SW
authors.lastname: Corso
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peppercorn
authors.forename: Steven M
authors.initials: SM
authors.lastname: Anderson
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Friedman
authors.forename: Evan T
authors.initials: ET
authors.lastname: Ogburn
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
authors.forename: James P
authors.initials: JP
authors.lastname: Evans
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Carey
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005240:Feasibility Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D013629:Tamoxifen / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6