title: The Effect of Tamoxifen Dose Increment in Patients With Impaired CYP2D6 Activity.
abstract: BACKGROUND
  The effect of tamoxifen dose elevation on endoxifen serum concentration was investigated in patients with reduced CYP2D6 activity resulting from genetic variation and/or CYP2D6 inhibitor use. Additionally, baseline differences in endoxifen concentrations between the different CYP2D6 phenotypes were studied.
  
  
  METHODS
  Patients, treated with tamoxifen 20 mg once daily (QD) for at least 4 weeks, were classified as phenotypic extensive (EM), intermediate (IM), or poor (PM) metabolizer based on their genotype and comedication. In patients with an IM or PM phenotype, the tamoxifen dose was increased to 40 mg QD for 4 weeks. Tamoxifen, 4-OH-tamoxifen, N-desmethyltamoxifen, and endoxifen serum concentrations were measured at baseline and 4 weeks after the dose increment. Side effects of tamoxifen were assessed using the validated Functional Assessment of Cancer Therapy-Endocrine Symptom subscale (FACT-ESS-19).
  
  
  RESULTS
  The median baseline endoxifen concentration differed between EMs (11.4 mcg/L: n = 19), IMs (8.3 mcg/L: n = 16), and PMs (4.0 mcg/L: n = 7), P = 0.040. Tamoxifen dose elevation significantly increased the median endoxifen concentrations in 12 IMs from 9.5 to 17.4 mcg/L (P < 0.001) and in 4 PMs from 3.8 to 7.8 mcg/L (P = 0.001), without influencing median FACT-ESS-19 scores.
  
  
  CONCLUSIONS
  Raising the tamoxifen dose to 40 mg QD significantly increased endoxifen concentrations in IMs and PMs without increasing side effects. The tamoxifen dose increment in PMs was insufficient to reach endoxifen concentrations equal to those observed in EMs. Future studies will clarify the direct effect of endoxifen exposure on tamoxifen efficacy and may reveal a threshold endoxifen concentration that is critical for its efficacy.
authors.affiliation: *Department of Pharmacy, Radboud University Medical Center, Nijmegen; †Department of Clinical Oncology; ‡Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center; §Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam; ¶Department of Medical Oncology, Radboud University Medical Center, Nijmegen; and ‖Department of Medical Oncology, Academic Medical Center, University of Amsterdam, the Netherlands.
authors.forename: Marieke E B
authors.initials: ME
authors.lastname: Welzen
authors.forename: Vincent O
authors.initials: VO
authors.lastname: Dezentjé
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: Angela P H
authors.initials: AP
authors.lastname: Colbers
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.forename: Nielka P
authors.initials: NP
authors.lastname: van Erp
authors.forename: Jan
authors.initials: J
authors.lastname: den Hartigh
authors.forename: David M
authors.initials: DM
authors.lastname: Burger
authors.forename: Hanneke W M
authors.initials: HW
authors.lastname: van Laarhoven
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D013629:Tamoxifen / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6