Composite functional genetic and comedication CYP2D6 activity score in predicting tamoxifen drug exposure among breast cancer patients.

Silvana Borges, Zeruesenay Desta, Yan Jin, Azzouz Faouzi, Jason D. Robarge, Sanosh Philips, Anne Nguyen, Vered Stearns, Daniel Hayes, James M. Rae, Todd Skaar, David A. Flockhart, Lang Li

Research output: Contribution to journalArticle

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Abstract

Accurate assessment of CYP2D6 phenotypes from genotype is inadequate in patients taking CYP2D6 substrate together with CYP2D6 inhibitors. A novel CYP2D6 scoring system is proposed that incorporates the impact of concomitant medications with the genotype in calculating the CYP2D6 activity score. Training (n = 159) and validation (n = 81) data sets were obtained from a prospective cohort tamoxifen pharmacogenetics registry. Two inhibitor factors were defined: 1 genotype independent and 1 genotype based. Three CYP2D6 gene scoring systems, and their combination with the inhibitor factors, were compared. These 3 scores were based on Zineh, Zanger, and Gaedigk's approaches. Endoxifen/NDM-Tam plasma ratio was used as the phenotype. The overall performance of the 3 gene scoring systems without consideration of CYP2D6-inhibiting medications in predicting CYP2D6 phenotype was poor in both the training set (R(2) = 0.24, 0.22, and 0.18) and the validation set (R(2) = 0.30, 0.24, and 0.15). Once the CYP2D6 genotype-independent inhibitor factor was integrated into the score calculation, the R(2) values in the training and validation data sets were nearly twice as high as the genotype-only scoring model: (0.44, 0.43, 0.38) and (0.53, 0.50, 0.41), respectively. The integration of the inhibitory effect of concomitant medications with the CYP2D6 genotype into the composite CYP2D6 activity score doubled the ability to predict the CYP2D6 phenotype. However, endoxifen phenotypes still varied substantially, even with incorporation of CYD2D6 genotype and inhibiting factors, suggesting that other, as yet unidentified factors must be involved in tamoxifen activation.

Original languageEnglish (US)
Pages (from-to)450-458
Number of pages9
JournalJournal of Clinical Pharmacology
Volume50
Issue number4
StatePublished - Apr 2010
Externally publishedYes

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Cytochrome P-450 CYP2D6
Tamoxifen
Breast Neoplasms
Genotype
Pharmaceutical Preparations
Phenotype
Pharmacogenetics
Genes
Registries

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Composite functional genetic and comedication CYP2D6 activity score in predicting tamoxifen drug exposure among breast cancer patients. / Borges, Silvana; Desta, Zeruesenay; Jin, Yan; Faouzi, Azzouz; Robarge, Jason D.; Philips, Sanosh; Nguyen, Anne; Stearns, Vered; Hayes, Daniel; Rae, James M.; Skaar, Todd; Flockhart, David A.; Li, Lang.

In: Journal of Clinical Pharmacology, Vol. 50, No. 4, 04.2010, p. 450-458.

Research output: Contribution to journalArticle

Borges, S, Desta, Z, Jin, Y, Faouzi, A, Robarge, JD, Philips, S, Nguyen, A, Stearns, V, Hayes, D, Rae, JM, Skaar, T, Flockhart, DA & Li, L 2010, 'Composite functional genetic and comedication CYP2D6 activity score in predicting tamoxifen drug exposure among breast cancer patients.', Journal of Clinical Pharmacology, vol. 50, no. 4, pp. 450-458.
Borges, Silvana ; Desta, Zeruesenay ; Jin, Yan ; Faouzi, Azzouz ; Robarge, Jason D. ; Philips, Sanosh ; Nguyen, Anne ; Stearns, Vered ; Hayes, Daniel ; Rae, James M. ; Skaar, Todd ; Flockhart, David A. ; Li, Lang. / Composite functional genetic and comedication CYP2D6 activity score in predicting tamoxifen drug exposure among breast cancer patients. In: Journal of Clinical Pharmacology. 2010 ; Vol. 50, No. 4. pp. 450-458.
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