Biomedical Engineering Reference
In-Depth Information
All these drugs, some of them accompanied with diagnostic tests aiming at
preselecting patients who are more likely to respond to anticancer treatment [
5
] ,
constitute vivid examples of the emerging field of personalized medicine [
6,
7
] . In
that context, since most TKIs are also characterized by an important interindividual
variability in their pharmacokinetics (PK), increasing efforts for treatment optimi-
zation should be made for targeting adequate drug exposure in patients, increasing
thereby the likelihood of optimal clinical response and tolerability of anticancer
treatment. This can be done through the Therapeutic Drug Monitoring (TDM)
approach, whereby the careful selection of TKI dosage is adapted to each patient
according to individual plasma levels, contributing to minimize the risk of major
adverse reactions and to increase the probability of efficient, long-lasting, therapeutic
response [
8,
9
] .
Conversely, although clinically used for more than 30 years, it has been less than
a decade ago that several publications have reported that the clinical efficacy of
tamoxifen, the first and most widely used targeted therapy for estrogen-sensitive
breast cancer, may depend on the formation of the active metabolites 4-hydroxy-
tamoxifen and 4-hydroxy-
N
-desmethyl-tamoxifen (endoxifen) [
10
] . Large interin-
dividual variability in endoxifen plasma concentrations has been observed and
related both to genetic and environmental (i.e., drug-induced) factors altering
CYP450s metabolizing enzymes activity [
11
]. Since endoxifen is considered to be
responsible for an important part of the in vivo pharmacological activity of tamox-
ifen [
10
], there is a growing interest for monitoring endoxifen plasma concentra-
tions in breast cancer patients. Whether this would constitute a valid approach to
optimize individual tamoxifen dosage remains however to be formally demonstrated
in randomized clinical trials (RCTs).
Implementation of a routine TDM program for both TKIs and tamoxifen/endox-
ifen necessitates the access to suitable instrumental technology, bioanalytical exper-
tise, and definite knowledge in clinical pharmacokinetics for drug level interpretation
leading possibly to dosage adjustment. The analytical results, integrated with the clin-
ical observations, may influence the therapeutic intervention and in turn, clinical out-
come. Reliability of analytical methods is therefore a critical issue, justifying the
efforts and time devoted to their thorough validation and to extensive characterization
of their performance (i.e., precision, accuracy, robustness, and turnaround time).
Initially, high performance liquid chromatography techniques coupled to ultraviolet
detection (HPLC-UV) have been developed for the measurement of imatinib [
12
] and
other TKIs in biological fluids. At present, however, because of its unsurpassed selec-
tivity and sensitivity, HPLC or Ultra performance liquid chromatography (UPLC)
coupled to tandem triple quadrupole Mass Spectrometry (LC-MS/MS) has become
the method of choice for drug plasma level measurements and is extensively applied
for early and more recent TKIs. These powerful analytical technologies are becoming
accessible to an increasing number of Academic Hospital Centers for TDM clinical
service and research projects. These LC-MS/MS assays can bring invaluable informa-
tion on patients' drug exposure and contribute, in conjunction with patient's pharma-
cogenetic tests as well as tumor genetic profiles determination, to the reinforcement
and refinement of the personalized anticancer drug prescription.
