Biomedical Engineering Reference
In-Depth Information
4
Discussion and Conclusions
An increasing body of evidence is accumulating for legitimating the blood monitor-
ing of targeted anticancer TKIs and tamoxifen metabolites profiles, especially given
their high interindividual pharmacokinetic variability, due to influences of co-med-
ications, diet, and comorbidities, in addition to patients' genetic constitution.
Overall, the analytical developments by mass spectrometry have been instrumen-
tal (1) for the development of initial population pharmacokinetics-pharmacody-
namics models for some targeted anticancer drugs (mostly imatinib), possibly also
integrating the underlying patients' pharmacogenetic background and (2) for being
able to respond to clinically relevant issues on drug interaction problems with first-
generation targeted anticancer agents [
63
]. At present, however, it must be acknowl-
edged that the information on the relationships existing between the pharmacokinetics,
pharmacodynamics, and in some cases pharmacogenetics, is for most TKIs fre-
quently lacking, or supported by a limited number of—often anecdotal—studies.
Therapeutic intervals remain therefore to be determined for the majority of TKIs,
and PK-PD studies are best suited to that endeavor. Renewed translational efforts
integrating population pharmacokinetics analysis and patients' clinical responses
should therefore be carried out in the field of targeted anticancer therapy. Once
established, they should open the way to randomized clinical trials for formally vali-
dating the clinical usefulness of TDM for TKIs dosage adjustment, before being
integrated into standard of care. This raises ethical concerns, as once analytical
methods have been developed, clinicians are usually reluctant to deny control
patients group to TDM service. Alternate study designs should thus be considered,
such as comparison of “routine” TDM (i.e., done even in the absence of clinical
problems) versus a “rescue” TDM (done in case of unsatisfactory clinical response
or adverse events) [
266
] .
Even though not yet validated by RCTs for approved or more recent anticancer-
targeted agents, TDM can already be expected to bring clinically useful information
for the optimal management of selected cancer patients, e.g., in case of less-than-
optimal clinical response, occurrence of adverse side effects, treatment initiation in
the presence of interacting agents, or questionable compliance. For example, TDM
appears to be presently used to a rather large extent for the first TKI imatinib, based
on recommendations about target plasma levels to maintain for optimal clinical
response. Nevertheless, results from randomized controlled studies about TDM use-
fulness are still eagerly expected for this TKI [
266
]. This is no less the case for all
the more recent TKIs as well as for tamoxifen and its metabolites.
The TDM of TKIs is thus likely to become a very rapidly evolving field, with
new targeted anticancer agents approved at a regular pace. Further developments for
the TDM of several new TKIs are therefore anticipated to occur within the next few
years. In that context, not only a facilitated access to powerful mass spectrometry
instruments, but also the availability of robust methodologies for TKIs and tamox-
ifen/metabolites analysis is a necessity for academic hospital centers that provide
TDM service for targeted anticancer therapy. In particular, bioanalytical methods
