Regular Article

British Journal of Cancer (2001) 85, 317–324. doi:10.1054/bjoc.2001.1925 www.bjcancer.com
Published online 31 July 2001

Pharmacokinetics of anastrozole and tamoxifen alone, and in combination, during adjuvant endocrine therapy for early breast cancer in postmenopausal women: a sub-protocol of the 'Arimidex™ and Tamoxifen Alone or in Combination' (ATAC) trial

The ATAC Trialists' Group1,*

1CRC and UCL Cancer Trials Centre, University College London, Stephenson House, 158-160 N Gower Street, London, NW1 2ND, UK

*Contributors to the trial are listed in Appendices I, II, and III in the Acknowledgements section.

Received 20 September 2000; Revised 22 April 2001; Accepted 2 May 2001.

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Abstract

The ATAC trial evaluates in a randomized, double-blind design, Arimidex™ (anastrozole) alone or in combination with tamoxifen, relative to tamoxifen alone as 5-year adjuvant treatment in postmenopausal women with early breast cancer. Patients included in the pharmacokinetic (PK) sub-protocol had been in ATAC for greater than or equal to3 months, taking their medication in the morning and were 100% compliant for the preceding 14 days. Blood samples were collected 24 plusminus 4 h after last dose. Trough (Cmin) plasma concentrations of anastrozole, tamoxifen and desmethyltamoxifen (DMT) were measured by validated methods. The PK results were based on a total of 347 patients (131 anastrozole (1 mg o.d.), 111 tamoxifen (20 mg o.d.), 105 anastrozole and tamoxifen (1 and 20 mg o.d. respectively)). The geometric mean steady-state trough plasma concentrations of tamoxifen and DMT were statistically equivalent in patients receiving tamoxifen alone or in combination with anastrozole: geometric mean tamoxifen = 94.8 ng ml–1and 95.3 ng ml–1in tamoxifen alone and combination groups, respectively; geometric mean DMT = 265.1 and 277.6 ng ml-1in the tamoxifen and anastrozole and tamoxifen groups, respectively. The geometric mean anastrozole levels were 27% lower (90% Cl 20–33%; P < 0.001) in the presence of tamoxifen than with anastrozole alone. Baseline plasma oestradiol levels were not obtained in the PK sub-protocol, however, such information was available from a similar ATAC sub-protocol, which evaluated bone mineral density. Mean oestradiol levels were 21.3, 19.3, and 21.6 pmol l-1prior to treatment and 3.7, 20.9 and 3.6 pmol l-1after 3 months in the anastrozole, tamoxifen, and combination groups, respectively (n = 167). On-treatment values were below the detection limit (3 pmol l-1) in 43.6 and 38.5% of the anastrozole alone and anastrozole in combination with tamoxifen groups, respectively. As a result of (a) the lack of effect of anastrozole on tamoxifen and DMT levels and (b) the observed fall in blood anastrozole levels having no significant effect on oestradiol suppression by anastrozole, we conclude that the observed reduction in anastrozole levels by tamoxifen is unlikely to be of clinical significance when anastrozole and tamoxifen are administered together. © 2001 Cancer Research Campaign

Keywords:

arimidex, tamoxifen, aromatase inhibitor, oestrogen, oestradiol, breast cancer

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