Tamoxifen pharmacokinetics

Lim HS, Lee HJ, Lee KS, Lee ES, Jang IJ, Ro J (2007) Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol 25 3837-3845... 

Anastrozole is a selective nonsteroidal aromatase inhibitor that lowers estrogen levels. The pharmacokinetics of anastrozole demonstrate good absorption, with hepatic metabolism the primary route of elimination and only 10% excreted unchanged by the kidney. The elimination half-life is approximately 50 hours. Anastrozole is used for the adjuvant treatment of postmenopausal women with hormone-positive breast cancer and in breast cancer patients who have had disease progression following tamoxifen. Side effects include hot flashes, arthralgias, osteoporosis/bone fractures, and thrombophlebitis. 

Raloxifene, a more complete uterine antagonist than tamoxifen or clomiphene, significantly reduces leiomyoma size in post-menopausal women [31], yet it is less efficacious at reducing tumor volume in pre-menopausal women [32], This result has been attributed to the poor pharmacokinetic properties of this compound in which extensive conjugative metabolism of the phenol(s) limits the circulating levels of the parent drug. In addition, clinical outcomes in premenopausal women treated with raloxifene suggest that this compound, like tamoxifen and clomiphene, can affect the ovaries via the HPO axis [33]. These data, taken collectively, indicate that current SERMs lack the efficacy, pharmacokinetic, and ovarian safety properties needed to treat leiomyoma in ovulatory women. 

In 34 post-menopausal women with early breast cancer anastrozole 1 mg/day for 28 days had no effect on the pharmacokinetics of tamoxifen 20 mg/day (38). 

Dowsett M, Tobias JS, Howell A, Blackman GM, Welch H, King N, Ponzone R, von Euler M, Baum M. The effect of anastrozole on the pharmacokinetics of tamoxifen in postmenopausal women with early breast cancer. Br J Cancer 1999 79(2) 311-5. 

Dowsett M, Pfister C, Johnston SR, Miles DW, Houston SJ, Verbeek JA, Gundacker H, Sioufi A, Smith IE. Impact of tamoxifen on the pharmacokinetics and endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast cancer. Clin Cancer Res 1999 5(9) 2338-43. 

This chapter reviews the bioanalytical developments by mass spectrometry in the field of targeted anticancer therapy, across the growing family of recent FDA-approved oral TKIs as well as tamoxifen and its active metabolites. The text also provides an introduction to existing pharmacokinetics-pharmacodynamics knowledge in the field of targeted anticancer therapy. 

Various hyphenated LC-MS-based assays, using either the electrospray ionization (ESI) or the atmospheric pressure chemical ionization (APCI) interface, have been developed and applied in the clinical setting in order to support pharmacokinetic (PK), pharmacogenetic-pharmacokinetic (PG-PK), and pharmacokinetic-pharmacodynamic (PK-PD) studies in BC patients under tamoxifen therapy (Table 3). 

To sum up, there is a great heterogeneity in the described methods that have so far been developed and, for the great majority of them, used in the clinical setting to support pharmacogenetic-pharmacokinetic-pharmacodynamic (PG-PK-PD) studies. Of these methods, only the most recent fully validated ones that have proven enough accuracy, precision, robustness, and selectivity seems to be reliable and suitable for measuring exposure of tamoxifen and its metabolites in tamoxifen-treated breast cancer patients. 

Kiyotani K et al (2012) Pharmacogenomics of tamoxifen roles of drug metabolizing enzymes and transporters. Drug Metab Pharmacokinet 27(1) 122—131... 

Robertson DW, Katzenellenbogen JA, Long DJ, Rorke EA, Katzenellenbogen BS (1982) Tamoxifen antiestrogens - a comparison of the activity, pharmacokinetics, and metabolic-activation of the cis-isomer and trans-isomer of tamoxifen. J Steroid Biochem 16 1-13... 

Pharmacokinetics Tamoxifen is effective on oral administration. It is partially metabolized by the liver. Some metabolites possess antagonist activity while others have agonist activity. Unchanged drug and its metabolites are excreted predominantly through the bile into feces. 

Lawrence, J.A., Adamson, P.C., Caruso, R., Chow, C., Kleiner, D., Murphy, R.F., Venzon, D.J., Shovlin, M., Noone, M., Merino, M., Cowan, K.H., Kaiser, M., O Shaughnessy, J. and Zujewski, J. (2001) Phase I clinical trial of alitretinoin and tamoxifen in breast cancer patients toxicity, pharmacokinetic, and biomarker evaluations. Journal of Clinical Oncology, 19, 2754-2763. 

The ATAC Trialists Group, Pharmacokinetics of Anastrozole and Tamoxifen Alone, and in Combination, During Adjuvant Endocrine Therapy for Early Breast Cancer in Postmenopausal Women A Suh-Protocol of the Arimidex and Tamoxifen Alone or in Combination (ATAC) Trial, British Journal of Cancer 85 (2001) 317-324-... 

Tamoxifen appears to have no significant effect on the pharmacokinetics of doxorubicin. 

A pharmacokinetic study in patients with non-Hodgkin s lymphoma receiving CHOP (cyclophosphamide, vincristine, prednisone and doxorubicin 37.5 to 50 mg/m ) found that the addition of tamoxifen 480 mg daily for 5 days had no significant effect on the AUC or total clearance of doxorubicin. For the possible additive thromboembolic effect of doxorubicin and tamoxifen, see Antineoplastics + Tamoxifen , p.616. 

El-Y arigi A, Berry J, Ezzat A, Wahab FA. Effect of tamoxifen on the pharmacokinetics of doxorubicin in patients with non-Hodgkin s l3nnphoma. TherDrugMonit( 991) 19,632-6. 

In 6 menopausal women with breast cancer aminoglutethimide 250 mg four times daily for 6 weeks markedly reduced the serum levels of tamoxifen 20 to 80 mg daily and most of its metabolites. The clearance of the tamoxifen was inereased by 3.2-fold and the tamoxifen AUC was re-dueed by 73% (range 56 to 80%). Conversely, the concurrent use of anastrozole 1 mg daily for 28 days did not affect the pharmacokinetics of tamoxifen in a double-blind, placebo-controlled study in 34 women with breast eaneer who had been taking tamoxifen 20 mg daily for at least 10 weeks. Similarly, letrozole 2.5 mg daily had no effeet on the pharma-eokineties of tamoxifen in 18 women taking tamoxifen 20 mg daily. Further, a study in 32 women clinically disease-free following primary treatment for breast eaneer and who had been taking tamoxifen 20 mg daily for at least 4 months found that exemestane 25 mg daily for 8 weeks... 

Tamoxifen 20 to 80 mg daily did not alter the pharmacokineties of aminoglutethimide 250 mg four times daily. In a pilot study, 18 postmenopausal women with breast cancer were gi ven exemestane 25 mg daily for 14 days, then exemestane and tamoxifen 20 mg daily for 4 weeks. Tamoxifen did not affect the pharmacokinetics (plasma levels) or pharmacodynamics (estrone, estrone sulfate and estradiol suppression) of exemestane and the eombination was well-tolerated. In 12 women letrozole levels were reduced by 38% (range 0 to 70%) 6 weeks after tamoxifen 20 mg daily was added to letrozole 2.5 mg daily. This redue-tion persisted after 4 to 8 months however, the estradiol suppressant effeets of letrozole did not appear to be affected. Similarly, although the estradiol suppressant effects of anastrozole 1 mg daily did not appear to be affeeted by tamoxifen 20 mg daily in two studies, in one of these studies, anastrozole levels were deereased by 27% by tamoxifen. ... 

Theoretically, the combination of an oestrogen antagonist such as tamoxifen and an aromatase inhibitor should provide additional benefit in the treatment of hormone-dependent cancers, however, no clinical studies have yet found this to be so. The pharmacokinetic interactions described above may partly explain this. It may be preferable to use these drugs sequentially rather than concurrently. ... 

Ingle JN, Suman VJ, Johnson PA, Krook JE, Mailliaid lA, Wheeler Lc ninzi CX, Perez EA, Jordan VC, Dowsett M. Evaluatiem of tamoxifen plus letro le with assesanent of pharmacokinetic interaction in postmenopausal women with metastatic breast cancer. CUn Caicer Res (1999) 5,1642-9. 

Rivera E, Valero V, Francis D, Asnis AG, SchaafLJ, Duncan B,Hoitobagyi GN. Pilot stutfy evaluating the pharmacokinetics, i iarmacotfynamicsi, and safety of the cembination of exemestane and tamoxifen. Clin Cancer Res (2004) 10,1943-8. 

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