Pharmacogenomic-pharmacokinetic study of selective estrogen-receptor modulators with intra-patient dose escalation in breast cancer.
Adult
Aged
Aged, 80 and over
Breast Neoplasms
/ drug therapy
Cytochrome P-450 CYP2C19
/ genetics
Cytochrome P-450 CYP2D6
/ genetics
Cytochrome P-450 CYP2D6 Inhibitors
/ therapeutic use
Female
Genotype
Hot Flashes
/ etiology
Humans
Hydroxylation
Middle Aged
Phenotype
Polymorphism, Genetic
Selective Estrogen Receptor Modulators
/ administration & dosage
Smoking
Tamoxifen
/ analogs & derivatives
Toremifene
/ administration & dosage
Breast cancer
CYP2D6
Pharmacokinetics
Tamoxifen
Toremifene
Journal
Breast cancer (Tokyo, Japan)
ISSN: 1880-4233
Titre abrégé: Breast Cancer
Pays: Japan
ID NLM: 100888201
Informations de publication
Date de publication:
Sep 2019
Sep 2019
Historique:
received:
14
06
2018
accepted:
03
02
2019
pubmed:
9
2
2019
medline:
1
1
2020
entrez:
9
2
2019
Statut:
ppublish
Résumé
An association between CYP2D6 polymorphisms and tamoxifen (TAM) efficacy has not been confirmed, partly due to unreliable prediction of active metabolite exposure solely by CYP2D6 activity. The efficacy of TAM dose escalation appears limited in poor TAM metabolizers. Since the chlorine atom on the side chain of toremifene (TOR) prevents 4-hydroxylation by CYP2D6, its contribution to active conversion of TOR is minor. We examined the role of TOR and its dose escalation among poor TAM metabolizers. The pharmacokinetics (PK) and pharmacogenomics (PGx) of TAM and TOR were studied. Correlation between PK and CYP2D6 inhibitor use, smoking status, and PGx were examined by regression analysis. For patients showing low endoxifen levels, an intra-patient dose escalation of TOR was conducted, and TOR was increased from 40 to 120 mg for ≥ 24 weeks with PK sampling. Total activity was calculated as the sum of the concentration of each active metabolite adjusted by their respective in vitro activities. Fifty and 11 of the 273 participating patients had endoxifen levels < 15 and < 7.5 ng/mL, respectively. The CYP2D6 genotype was the major determinant for TAM activity (p < 0.01). Smoking status (p = 0.07) and the CYP2C19 phenotype (p = 0.07), but not the CYP2D6 genotype (p = 0.61), showed marginally significant effects on TOR activity. TOR activity increased significantly with dose escalation, even among poor TAM metabolizers, and was maintained for ≥ 24 weeks. TOR might be a valid alternative to TAM in patients predicted to be poor TAM metabolizers.
Sections du résumé
BACKGROUND
BACKGROUND
An association between CYP2D6 polymorphisms and tamoxifen (TAM) efficacy has not been confirmed, partly due to unreliable prediction of active metabolite exposure solely by CYP2D6 activity. The efficacy of TAM dose escalation appears limited in poor TAM metabolizers. Since the chlorine atom on the side chain of toremifene (TOR) prevents 4-hydroxylation by CYP2D6, its contribution to active conversion of TOR is minor. We examined the role of TOR and its dose escalation among poor TAM metabolizers.
METHODS
METHODS
The pharmacokinetics (PK) and pharmacogenomics (PGx) of TAM and TOR were studied. Correlation between PK and CYP2D6 inhibitor use, smoking status, and PGx were examined by regression analysis. For patients showing low endoxifen levels, an intra-patient dose escalation of TOR was conducted, and TOR was increased from 40 to 120 mg for ≥ 24 weeks with PK sampling. Total activity was calculated as the sum of the concentration of each active metabolite adjusted by their respective in vitro activities.
RESULTS
RESULTS
Fifty and 11 of the 273 participating patients had endoxifen levels < 15 and < 7.5 ng/mL, respectively. The CYP2D6 genotype was the major determinant for TAM activity (p < 0.01). Smoking status (p = 0.07) and the CYP2C19 phenotype (p = 0.07), but not the CYP2D6 genotype (p = 0.61), showed marginally significant effects on TOR activity. TOR activity increased significantly with dose escalation, even among poor TAM metabolizers, and was maintained for ≥ 24 weeks.
CONCLUSION
CONCLUSIONS
TOR might be a valid alternative to TAM in patients predicted to be poor TAM metabolizers.
Identifiants
pubmed: 30734152
doi: 10.1007/s12282-019-00952-9
pii: 10.1007/s12282-019-00952-9
pmc: PMC6694038
doi:
Substances chimiques
Cytochrome P-450 CYP2D6 Inhibitors
0
Selective Estrogen Receptor Modulators
0
Tamoxifen
094ZI81Y45
4-hydroxy-N-desmethyltamoxifen
46AF8680RC
Toremifene
7NFE54O27T
Cytochrome P-450 CYP2C19
EC 1.14.14.1
Cytochrome P-450 CYP2D6
EC 1.14.14.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
535-543Subventions
Organisme : Japan Breast Cancer Research Group
ID : JBCRG12
Organisme : Japan Breast Cancer Research Group
ID : JBCRG15
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