Pronounced Interindividual But Not Intraindividual Variation in Tamoxifen and Metabolite Levels in Plasma During Adjuvant Treatment of Women With Early Breast Cancer.
BACKGROUND
Tamoxifen is still an important antihormonal treatment option for patients with breast cancer and estrogen receptor-positive tumors. More than 20% of patients relapse despite treatment. The drug is usually dosed 20 mg/d irrespective of interindividual variation in drug clearance. To study interindividual and intraindividual variation in plasma levels we measured tamoxifen and metabolite levels in plasma on 2 occasions, with at least 4 weeks in between, of 39 women (19 premenopausal and 20 postmenopausal women) on adjuvant treatment (20 mg/d) of early breast cancer.


METHODS
We used an ultra-performance liquid chromatography with a mass spectrometry detection method for identification and quantification of tamoxifen, N-desmethyltamoxifen, 4-OH-tamoxifen, and endoxifen. Follicle-stimulating hormone, luteinizing hormone, and estradiol levels were also measured.


RESULTS
The plasma concentrations of tamoxifen and its metabolites showed a pronounced interindividual variation, whereas intraindividual concentrations were rather stable. Despite the same dosage, interindividual tamoxifen concentrations varied from 51 to 307 ng/mL (124 ± 57, mean ± SD) and endoxifen values showed a range from 3.2 to 19 ng/mL (10.4 ± 5.2, mean ± SD), that is, 6-fold variation for both.


CONCLUSIONS
Large interindividual variation of tamoxifen and endoxifen with stable intraindividual levels, and too low levels of endoxifen in a considerable proportion of patients strongly support that therapeutic drug monitoring and individualized dosing could lead to optimal exposure and hopefully better outcome. A randomized outcome study between conventional dosing and therapeutic drug monitoring-guided dosing is needed to show whether this approach works.
*Department of Medicine, Clinical Pharmacology Unit, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden;†Department of Pharmacology, School of Medicine, University of Sulaimani, Kurdistan, Iraq;‡Department of Laboratory Medicine, Clinical Pharmacology Unit, Karolinska Institutet;§Department of Clinical Pharmacology, Karolinska Univeristy Hospital; and¶Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Alan K
AK
Fotoohi
Hazhar
H
Karim
Pierre
P
Lafolie
Anton
A
Pohanka
Jennie
J
Östervall
Thomas
T
Hatschek
Sigurd
S
Vitols
D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000097:blood* / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004958:Estradiol / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000097:blood* / Q000627:therapeutic use*; D053719:Tandem Mass Spectrometry / Q000379:methods
D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; C028787:N-desmethyltamoxifen