No abstract

1 The effect of low dose steady state warfarin (0.2 mg and 1 mg daily) on clotting factor activity and vitamin K1 metabolism was studied in seven healthy volunteers. 2 Steady state plasma warfarin concentrations were 41‐99 ng ml‐1 for the 0.2 mg dose and 157‐292 ng ml‐1 for the 1 mg dose. 3 There was a significant prolongation of the mean prothrombin time (0.9 s) after 1 mg warfarin daily, but no significant change in prothrombin time after 0.2 mg warfarin daily. There was no significant change in individual clotting factor activity (II, VII, IX or X) with either dose of warfarin. 4 Following the administration of a pharmacological dose of vitamin K1 (10 mg), all seven volunteers had detectable levels of vitamin K1 2,3‐epoxide with both doses of warfarin (Cpmax 31‐409 ng ml‐1). 5 Both the Cpmax and the AUC for vitamin K1 2,3‐ epoxide were significantly greater on 1 mg of warfarin daily than 0.2 mg daily (P less than 0.01). 6 The apparent dissociation between inhibition of vitamin K1 2,3‐epoxide reductase and reduction of clotting factor activity, produced by warfarin, may reflect the insensitivity of functional clotting factor assays to a small reduction in clotting factor concentration.

Background. A number of studies have provided widely heterogeneous results for and against the hypothesis that genetic variants in drug metabolizing enzymes can influence patient response to tamoxifen. Most of these studies are confounded by relatively small numbers of patients, lack of comprehensive genotype information, lack of detailed clinical outcome data, and patient selection biases. The ATAC trial was a prospective randomized double-blind placebo-controlled trial designed to compare the adjuvant use of anastrozole versus tamoxifen for 5 years. The trial's detailed efficacy and safety data, long term (10-year) follow-up and high number of events make it an ideal setting for pharmacogenetic analyses. Here we report our initial findings testing for correlations with SNPs in CYP2D6 and UGT2B7, the primary enzymes responsible for the presumed activation and inactivation of tamoxifen, respectively, with clinical outcomes including any disease recurrence, distant recurrence, and overall survival. Methods: CYP2D6 genotype data for the 7 most common alleles were used to assign each patient a ‘score’ based on predicted allele activities from 0 (no activity) to 2 (high activity). Patients were also tested for the UGT2B7*2 variant, which has lower enzymatic activity and has been shown to correlate with higher serum endoxifen concentrations. All genotype determinations were made without knowledge of the patient's treatment assignment or outcomes. Results: Comprehensive CYP2D6 genotype data were obtained on 588 and 615 patients randomized to receive tamoxifen, and anastrozole, respectively. After median 10 years of follow-up, there were 115 recurrences in the tamoxifen cohort. We found no associations between any of the CYP2D6 scores and rates of recurrence in tamoxifen treated patients. A test for trend across CYP2D6 scores was not significant. In the anastrozole cohort, there were 92 recurrences, and there was no evidence of an association between CYP2D6 score with rates of recurrence. Likewise, there was no detectable association in either the tamoxifen or anastrozole group with UGT2B7 genotype alone or in combination with CYP2D6 score. Concomitant SSRI usage was recorded in these patients and is being assessed for possible impact on these results. Conclusion: These data from a large prospective clinical trial, with detailed outcome data and long-term follow-up do not support the hypothesis that patient with decreased CYP2D6 enzymatic activity receive less benefit from tamoxifen therapy compared to wild-type CYP2D6 patients. Variants in drug targets and estrogen signaling pathways may be the genetic basis for patient variability in anti-estrogen risk versus benefit profiles. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S1-7.