Biomedical Engineering Reference
In-Depth Information
that endoxifen concentrations among 2D6 wild-type patients who were 2D6 geno-
types and were on SSRIs had endoxifen concentrations that were as low as poor
metabolizers [
7
]. In a population-based study of 2,430 breast cancer patients treated
with tamoxifen, those on a single SSRI had an increased risk of cancer deaths [
8
] .
These and other investigators have strongly suggested the discontinuance of these
drugs. Patients may not readily disclose their antidepressant drug use to their oncol-
ogists due to the stigma associated with depression. While the information for SSRIs
is now well documented, there are many other potential 2D6 enzyme inhibitors that
are taken by breast cancer patients. Herbal medications in particular are widely used
and may have adverse effects on tamoxifen metabolism. While Wu et al. showed no
difference with self-reported soy food intake, there are many other herbals that have
not yet been tested [
9
]. In the absence of outcome evidence from clinical trials, there
may be a role in routine therapeutic drug monitoring for the active metabolite.
LC-MS measurement for the occult use of SSRI may also be warranted.
2.1.3
Analytical Assays and TDM Testing
LC/tandem MS assays for tamoxifen metabolites have been described by numerous
investigators and used for research purposes [
10-
12
] . Figure
1
shows a typical chro-
matogram for the analyses of these metabolites from a serum sample. Following
chronic administration of a standard 20 mg tamoxifen per day dosage on presum-
ably wild-type subjects, typical serum concentrations at steady state were 150
(±50) ng/mL for tamoxifen, 180 (±70) ng/mL for
N
-desmethytam, 2.5 (±1.2) ng/mL
for 4-hydroxytam, and 5.0 (±2.5) ng/mL for endoxifen [
10
] .
Assays for tamoxifen and its metabolites are currently not used for routine therapeutic
drug monitoring. Because the half-life of tamoxifen is long, TDM for tamoxifen has the
disadvantage over genotyping in that steady state concentrations are not reached for
2-3 months. A significant delay in prescribing the most effective adjuvant therapeutic regi-
men (i.e., tamoxifen vs. aromatase inhibitors) may have an impact on disease-free survival.
Therefore, a combination of genotyping and phenotyping might be the best approach.
Figure
2
shows a proposed algorithm combining the attributes of both strategies. This
scheme has not been clinically validated nor is it endorsed by any clinical practice groups.
An alternative use of TDM is to evaluate the effectiveness of increasing the tamoxifen dose
from the standard 20 to 40 mg/day for individuals who are intermediate metabolizers.
The National Cancer Institute is evaluating this protocol in a prospective trial [
13
] .
2.2
Clopidogrel
2.2.1
Pharmacology and Pharmacogenomics
Clopidogrel is part of the thienopyridine class of antiplatelet drugs that are widely
used to treat patients with cardiovascular disease. The American College of
Cardiology has recommended antiplatelet medications for patients after angioplasty
