Biomedical Engineering Reference
In-Depth Information
probably be considered in special clinical situations such as in case of less-than-
expected initial clinical response, disease recurrence, adverse drug reactions, drug
interaction problems, doubt on patient compliance, and in further defined clinical
conditions (pediatrics, renal and hepatic failure, etc.). However, further extensive
evaluation should be carried out in well-conducted clinical trials before systematic
TDM can be integrated into cancer patient's standard of care [
56
] . The recent expe-
rience with the TDM of anti-HIV drugs that has been adopted in the current medical
practice without a rigorous evaluation by RCTs of its impact on clinical response
and toxicity should be avoided. Most TKIs have just been introduced in the clinical
practice, and such window of opportunity should not be missed. The formal demon-
stration of the clinical usefulness of TDM in RCT for the first major TKI imatinib
may therefore constitute the initial step opening the way of a generalized TDM
program for all subsequent TKIs for the optimal management of anticancer-targeted
therapy [
16,
17,
19,
20
] .
2.5
Pharmacokinetic Variability, Concentration-Ef fi cacy
and Concentration-Toxicity Relationships for TKIs
This section presents an overview of the existing pharmacokinetics-pharmacody-
namics knowledge in the field of targeted anticancer therapy for the TKIs approved
or in late phase of clinical development. An excellent comprehensive review of the
clinical pharmacokinetics of the first eight TKIs has been already published [
57
] .
Addressing these aspects is relevant because besides significant variability in phar-
macokinetics, relationships between concentrations and efficacy and/or toxicity are
amongst the principal characteristics that must be met for considering a formal
TDM program.
2.5.1
Imatinib
Pharmacokinetic Variability
Imatinib is characterized by an important interpatient pharmacokinetic variability,
yielding trough plasma concentrations spreading over between 40 and 80 % under
standard dosing regimens [
15,
16,
19,
20,
42,
50,
58
] . The intraindividual vari-
ability is lower and does not exceed 30 % [
42
]. The high interindividual variability
in pharmacokinetics has been mostly related to differences in the distribution and
metabolism of this drug. Imatinib distribution is mainly influenced by plasma pro-
tein concentrations, as approximately 95 % of the drug binds to albumin and a -1
acid glycoprotein [
18,
59
]. The levels of a-1 acid glycoprotein are known to be
altered (i.e., increased) in case of infections, and in acute and chronic conditions
(cancer, etc.). Active transport mechanisms are also responsible for imatinib tissue
uptake (via the carrier human organic cation hOCT-1) and efflux from tissues and
