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CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increases endoxifen serum concentrations without increasing side effects.

Dezentjé VO, Opdam FL, Gelderblom H, Hartigh den J, Van der Straaten T, Vree R, Maartense E, Smorenburg CH, Putter H, Dieudonné AS, Neven P, Van de Velde CJ, Nortier JW, Guchelaar HJ - Breast Cancer Res. Treat. (2015)

Bottom Line: Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased endoxifen concentrations (p < 0.001; p = 0.002, respectively) without increasing side effects.CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increased endoxifen concentrations without increasing short-term side effects.Whether such tamoxifen dose escalation is effective and safe in view of long-term toxic effects is uncertain and needs to be explored.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands. v.dezentje@gmail.com.

ABSTRACT
Breast cancer patients with absent or reduced CYP2D6 activity and consequently low endoxifen levels may benefit less from tamoxifen treatment. CYP2D6 poor and intermediate metabolizers may need a personalized increased tamoxifen dose to achieve effective endoxifen serum concentrations, without increasing toxicity. From a prospective study population of early breast cancer patients using tamoxifen (CYPTAM: NTR1509), 12 CYP2D6 poor and 12 intermediate metabolizers were selected and included in a one-step tamoxifen dose escalation study during 2 months. The escalated dose was calculated by multiplying the individual's endoxifen level at baseline relative to the average endoxifen concentration observed in CYP2D6 extensive metabolizers by 20 mg (120 mg maximum). Endoxifen levels and tamoxifen toxicity were determined at baseline and after 2 months, just before patients returned to the standard dose of 20 mg. Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased endoxifen concentrations (p < 0.001; p = 0.002, respectively) without increasing side effects. In intermediate metabolizers, dose escalation increased endoxifen to levels comparable with those observed in extensive metabolizers. In poor metabolizers, the mean endoxifen level increased from 24 to 81 % of the mean concentration in extensive metabolizers. In all patients, the endoxifen threshold of 5.97 ng/ml (=16.0 nM) reported by Madlensky et al. was reached following dose escalation. CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increased endoxifen concentrations without increasing short-term side effects. Whether such tamoxifen dose escalation is effective and safe in view of long-term toxic effects is uncertain and needs to be explored.

No MeSH data available.


Related in: MedlinePlus

Tamoxifen metabolism. 4OHTam 4-hydroxytamoxifen, CYP cytochrome P450 isoenzyme, SULT sulfotransferase, UGT UDP-glucuronosyltransferase, NDMTamN-desmethyltamoxifen, NR1 nuclear receptor subfamily 1, PXR pregnane X receptor, CAR constitutive androstane receptor
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Fig1: Tamoxifen metabolism. 4OHTam 4-hydroxytamoxifen, CYP cytochrome P450 isoenzyme, SULT sulfotransferase, UGT UDP-glucuronosyltransferase, NDMTamN-desmethyltamoxifen, NR1 nuclear receptor subfamily 1, PXR pregnane X receptor, CAR constitutive androstane receptor

Mentions: Serum concentrations of tamoxifen and its metabolites were measured by using a high-performance liquid chromatography-tandem mass spectrometry (HPLC LC/MS/MS) assay for the detection of tamoxifen and three metabolites in human serum. The HPLC LC/MS/MS assay was developed and validated for the purpose of the CYPTAM study at the laboratory of Clinical Pharmacy and Toxicology at the Leiden University Medical Center and is similar to a previously described method [28]. Tamoxifen, N-desmethyltamoxifen (NDMTam), and the main active metabolites 4-hydroxytamoxifen (4OHTam) and 4-hydroxy-N-desmethyltamoxifen (endoxifen) were accurately detected and quantified (Fig. 1).Fig. 1


CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increases endoxifen serum concentrations without increasing side effects.

Dezentjé VO, Opdam FL, Gelderblom H, Hartigh den J, Van der Straaten T, Vree R, Maartense E, Smorenburg CH, Putter H, Dieudonné AS, Neven P, Van de Velde CJ, Nortier JW, Guchelaar HJ - Breast Cancer Res. Treat. (2015)

Tamoxifen metabolism. 4OHTam 4-hydroxytamoxifen, CYP cytochrome P450 isoenzyme, SULT sulfotransferase, UGT UDP-glucuronosyltransferase, NDMTamN-desmethyltamoxifen, NR1 nuclear receptor subfamily 1, PXR pregnane X receptor, CAR constitutive androstane receptor
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4589558&req=5

Fig1: Tamoxifen metabolism. 4OHTam 4-hydroxytamoxifen, CYP cytochrome P450 isoenzyme, SULT sulfotransferase, UGT UDP-glucuronosyltransferase, NDMTamN-desmethyltamoxifen, NR1 nuclear receptor subfamily 1, PXR pregnane X receptor, CAR constitutive androstane receptor
Mentions: Serum concentrations of tamoxifen and its metabolites were measured by using a high-performance liquid chromatography-tandem mass spectrometry (HPLC LC/MS/MS) assay for the detection of tamoxifen and three metabolites in human serum. The HPLC LC/MS/MS assay was developed and validated for the purpose of the CYPTAM study at the laboratory of Clinical Pharmacy and Toxicology at the Leiden University Medical Center and is similar to a previously described method [28]. Tamoxifen, N-desmethyltamoxifen (NDMTam), and the main active metabolites 4-hydroxytamoxifen (4OHTam) and 4-hydroxy-N-desmethyltamoxifen (endoxifen) were accurately detected and quantified (Fig. 1).Fig. 1

Bottom Line: Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased endoxifen concentrations (p < 0.001; p = 0.002, respectively) without increasing side effects.CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increased endoxifen concentrations without increasing short-term side effects.Whether such tamoxifen dose escalation is effective and safe in view of long-term toxic effects is uncertain and needs to be explored.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands. v.dezentje@gmail.com.

ABSTRACT
Breast cancer patients with absent or reduced CYP2D6 activity and consequently low endoxifen levels may benefit less from tamoxifen treatment. CYP2D6 poor and intermediate metabolizers may need a personalized increased tamoxifen dose to achieve effective endoxifen serum concentrations, without increasing toxicity. From a prospective study population of early breast cancer patients using tamoxifen (CYPTAM: NTR1509), 12 CYP2D6 poor and 12 intermediate metabolizers were selected and included in a one-step tamoxifen dose escalation study during 2 months. The escalated dose was calculated by multiplying the individual's endoxifen level at baseline relative to the average endoxifen concentration observed in CYP2D6 extensive metabolizers by 20 mg (120 mg maximum). Endoxifen levels and tamoxifen toxicity were determined at baseline and after 2 months, just before patients returned to the standard dose of 20 mg. Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased endoxifen concentrations (p < 0.001; p = 0.002, respectively) without increasing side effects. In intermediate metabolizers, dose escalation increased endoxifen to levels comparable with those observed in extensive metabolizers. In poor metabolizers, the mean endoxifen level increased from 24 to 81 % of the mean concentration in extensive metabolizers. In all patients, the endoxifen threshold of 5.97 ng/ml (=16.0 nM) reported by Madlensky et al. was reached following dose escalation. CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increased endoxifen concentrations without increasing short-term side effects. Whether such tamoxifen dose escalation is effective and safe in view of long-term toxic effects is uncertain and needs to be explored.

No MeSH data available.


Related in: MedlinePlus