Biomedical Engineering Reference
In-Depth Information
information on its analytical performance, and was subsequently adapted for
pharmacokinetic studies in cancer patients [
125
] .
So far, validated LC-MS/MS methods published for the assay of dasatinib in
human plasma also comprise the analysis of metabolites [
46,
126,
127
] .
Finally, to the best of our knowledge, there are, as yet, no analytical method vali-
dation reports for the assay of the latest TKIs pazopanib, bafetinib, cediranib, and
motesanib in human biological samples.
2.6.2
Methods for Quanti fi cation of TKIs and Metabolites
Up to now, most investigations on the pharmacokinetic-pharmacodynamic aspects
of TKIs therapies have focused almost exclusively on concentrations of the parent
TKI drug in plasma, considering it as the best pharmacokinetic marker of anticancer
drug exposure and, in case of higher levels, of toxicity. However, drug metabolites
resulting from complex mutual genetic and environmental influences can also con-
tribute to treatment outcome. The metabolite profile can be considered as a snapshot
on the phenotypic pattern of the metabolizing activity in a patient at a given time.
Unfortunately, integration of this aspect with pharmacokinetics has attracted little
attention so far in the field of TKIs therapy. Distinct metabolite profiling patterns
per se could play an important role in the toxicity, tolerability, and outcome of tar-
geted anticancer therapy.
In that context, the LC-MS/MS technology makes it possible to determine in
patients' plasma not only the parent drug but also metabolites. Such an approach has
been applied for the quantification of imatinib and its main active
N
-desmethyl
metabolite CGP 74588 in plasma [
104,
108
], for monitoring imatinib metabolites
profile in patients' plasma [
109
], and for metabolism studies on dasatinib [
46,
126,
127
]. Assays enabling the quantification of sunitinib and its n-desethyl metabolite
SU12662 [
113
] and, more recently, dasatinib and two active metabolites [
127
] have
also been published. Overall, exposures of pharmacologically active metabolites
in patients suggested that they are not expected to contribute significantly for the
in vivo activity.
2.6.3
Methods for Multiplex Quanti fi cation of TKIs
Plasma Measurements
Mass spectrometry detection qualifies for the simultaneous measurement of arrays
of structurally unrelated anticancer-targeted agents in a single analytical run.
Multiplex analyses offer, therefore, the advantage of the establishment of calibra-
tion curves for several TKIs simultaneously, resulting in an overall reduction in
analytical time, turnaround time, and costs [
128,
129
]. Analytical methods using a
simplified extraction procedure followed by simultaneous quantification of multiple
TKIs are more efficient for rapidly providing TDM results allowing real-time
