Biomedical Engineering Reference
In-Depth Information
among patients, except for fluid retention, nausea, musculoskeletal pain, rash,
myalgia, and anemia, which were more frequently reported by patients with higher
imatinib concentrations. Based on the overall 5-year data, only fluid retention, rash,
myalgia, and anemia were more frequently reported by the patients with higher
imatinib concentrations. These studies therefore suggest that some, but not all,
adverse events may be related to elevated imatinib plasma concentrations [
34
] .
TDM for imatinib probably represents therefore a clinically useful tool for pro-
viding valuable information for clinicians to investigate the absence of expected
clinical response, the occurrence of toxicity, drug-drug interaction problems, and to
assess patients' short-term adherence. At present, the level of proof for imatinib
TDM varies between “recommended” and “potentially useful” [
34
] . Whether TDM
is also beneficial for the other TKIs remains to be established, but can be anticipated
considering their pharmacokinetics characteristics and metabolic pathways and the
drug interaction potentials (see below).
2.5.2
Nilotinib
Pharmacokinetic Variability
The interpatient variability in exposure to nilotinib is 32-64 % for exact reasons
remaining yet to be explained [
44,
57
]. In the phase I dose escalation study, a satura-
tion of nilotinib serum levels was observed with doses ranging from 400 to 1,200 mg
daily. With the administration of daily doses at the steady-state level, the peak con-
centration and the area under the concentration-time curve increased among patients
receiving 50-400 mg of the drug and reached a plateau among patients receiving
more than 400 mg. A possible explanation might be that nilotinib gastrointestinal
absorption saturates at doses exceeding 400 mg [
71
] .
Concentration-Effect Relationship
The relationships between nilotinib plasma concentration and clinical efficacy (or
toxicity) have not been studied yet. Irrespective of nilotinib PK-PD per se, Saglio
et al. [
72
] showed that nilotinib at a dose of either 300 or 400 mg twice daily was
superior to imatinib in patients with newly diagnosed chronic-phase Philadelphia
chromosome-positive CML. At 12 months, the rates of major molecular response
for nilotinib were nearly twice that observed for imatinib. The rates of complete
cytogenetic response by 12 months were also significantly higher for nilotinib
than for imatinib [
72
]. No data have been published for nilotinib concentration-
toxicity relationships nor plasma target values to be achieved for optimal clinical
response.
The limited PK-PD information available at present for nilotinib does not
exclude, however, that this drug may be a good candidate for TDM.
