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Pharmacogenomic-pharmacokinetic study of selective estrogen-receptor modulators with intra-patient dose escalation in

Hiroshi Ishiguro1,2, Shinji Ohno3,4, Yutaka Yamamoto5,4

  • 1Department of Medical Oncology, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasushiobara, Tochigi, 329-2763, Japan. hishiguro@iuhw.ac.jp.

Breast Cancer (Tokyo, Japan)
|February 9, 2019
PubMed
Abstract

Insights

Toremifene (TOR) may be a viable alternative to tamoxifen (TAM) for individuals who are poor metabolizers of TAM. Dose escalation of TOR effectively increased its activity, even in poor TAM metabolizers, offering a potential therapeutic option.

Area of Science:

  • Pharmacogenomics
  • Drug Metabolism
  • Oncology

Background:

  • CYP2D6 genotype is a key determinant of tamoxifen (TAM) efficacy, but its predictive value is limited by unreliable active metabolite exposure.
  • Poor TAM metabolizers show limited benefit from TAM dose escalation.
  • Toremifene (TOR) metabolism is less dependent on CYP2D6, suggesting potential efficacy in poor TAM metabolizers.

Purpose of the Study:

  • To investigate the role of toremifene (TOR) and its dose escalation in patients who are poor metabolizers of tamoxifen (TAM).
  • To evaluate the pharmacokinetics (PK) and pharmacogenomics (PGx) of TAM and TOR in a diverse patient population.

Main Methods:

  • Studied PK and PGx of TAM and TOR in 273 patients.
  • Analyzed correlations between PK, CYP2D6 inhibitor use, smoking, and PGx using regression analysis.
  • Conducted intra-patient TOR dose escalation (40 to 120 mg) for patients with low endoxifen levels, with PK sampling.

Main Results:

  • CYP2D6 genotype significantly predicted TAM activity (p < 0.01).
  • Smoking and CYP2C19 phenotype showed marginal effects on TOR activity (p = 0.07), while CYP2D6 genotype did not (p = 0.61).
  • TOR activity significantly increased with dose escalation and was sustained for ≥24 weeks, even in poor TAM metabolizers.

Conclusions:

  • Toremifene (TOR) demonstrates potential as an alternative to tamoxifen (TAM) for poor metabolizers.
  • TOR dose escalation can effectively increase drug activity in this patient subgroup.
  • Further research into TOR's role in endocrine therapy is warranted.
Keywords:
Breast cancerCYP2D6PharmacokineticsTamoxifenToremifene

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