Correlation between tamoxifen elimination and biomarker recovery in a primary prevention trial

We have shown previously that a reduction from the conventional dose of tam oxifen is associated with a comparable modulation of circulating biomarkers , including insulin-like growth factor-I and cholesterol. In the present st udy, we have correlated serum tamoxifen elimination with biomarker recovery in healthy subjects completing a 5-year intervention period. Tamoxifen, N- desmethyltamoxifen, and biomarker levels were measured at 0 (baseline), 2, 4, and 6 weeks after completion of treatment in 23 healthy postmenopausal w omen allocated to tamoxifen 20 mg/day and in 6 women allocated to placebo. Mean ( SD) serum tamoxifen and N-desmethyltamoxifen concentrations were, re spectively, 141 +/- 50 and 226 +/- 77 ng/ml at baseline, 36 +/- 19 and 99 /- 46 at 2 weeks, 20 +/- 15 and 61 +/- 37 at 4 weeks, and 12 +/- 9 and 36 /- 26 at 6 weeks. Serum tamoxifen and N-desmethyltamoxifen half-lives were 9 and 13 days, respectively. Body mass index was associated positively with drug's serum half-life. Compared with baseline values, the percentage incr ease in total cholesterol, low-density lipoprotein cholesterol, and insulin -like growth factor-I 4 weeks after treatment completion was 5, 9, and 14%, respectively. No change during the 6-week period was observed in the place bo arm. Our findings indicate that the biomarker recovery is slower than se rum tamoxifen elimination, suggesting that low tamoxifen concentrations may still exert a biological effect. In addition, the prolonged half-life of t amoxifen and metabolite provides the rationale for a weekly administration of the drug in a preventive context. However, the clinical implications of our findings remain to be defined.