Biomedical Engineering Reference
In-Depth Information
cells (P-glycoprotein [P-gp]) [ 18, 60, 61 ]. The expression and activity of these drug
transporters is modulated both by genetic factors (polymorphisms affecting func-
tion and expression) and environmental influences. As previously mentioned, ima-
tinib is metabolized by CYP3A4, whose activity is genetically determined, as well
as likely to be inhibited or induced by various environmental factors (coadminis-
tered drugs [ 62, 63 ] or food). Low concentrations have been described with the
CYP3A4-inducing agents rifampicin, antiepileptics drugs, and St. John's Wort [ 63 ] .
Alternately, excessive plasma concentration of imatinib, associated with clinical
toxicity, has been reported during the coadministration of voriconazole, a known
CYP3A4 inhibitor [ 64 ]. Finally, poor adherence has been recognized as an impor-
tant additional source of pharmacokinetic variability [ 8 ] .
Concentration-Effect Relationship
Several studies have described a relationship between imatinib trough plasma con-
centrations and clinical response. Initially, Picard et al. [ 16 ] have shown that trough
plasma concentrations of imatinib are significantly higher in patients with com-
plete cytogenetic response (CCR, defined by the complete disappearance of the
Philadelphia positive cells) and a major molecular response (MMR, defined by a
3 log decrease of BCR-ABL transcripts). A trough level above 1,002 ng/ml was
then recommended for CML patients [ 16 ]. In the landmark IRIS study [ 65 ] , Larson
et al. [ 15 ] have retrospectively observed higher imatinib trough concentrations
1 month after treatment initiation in patients who showed a complete cytoge-
netic response and major molecular response, in comparison to patients without
cytogenetic or molecular response (cut-off: 1,000 ng/ml). These findings were
confirmed in other studies. Whereas target values may differ between studies,
most authors acknowledged the potential clinical value of TDM of imatinib in
CML patients [ 66- 70 ] .
In GIST, important findings are also emerging from studies examining the rela-
tionships between imatinib PK and response to treatment [ 9 ] . A pharmacokinetic
analysis from a clinical trial of imatinib in patients with unresectable or metastatic
GIST reveals a correlation between imatinib total exposure and clinical response.
Trough levels over 1,100 ng/ml predicted a better overall benefit rate [ 17 ] . Widmer
et al. [ 19, 20 ] showed that free trough level was correlated with a clinical benefit in
GIST patients, with responders having higher free levels than non-responders.
Target levels might further depend on tumor genetics [ 20 ] .
The threshold of effective concentrations of imatinib for optimal clinical
response remains to be clearly defined and validated in a prospective clinical trial.
It remains also possible that different thresholds exist for different levels of response
and cancer cell genetic profiles [ 58 ] .
Widmer et al. [ 19, 20 ] demonstrated that both total (in GIST) and free drug expo-
sure (in CML and GIST) correlated with the occurrence and number of side effects.
Moreover, the study of Larson et al. [ 15 ] showed that during the first 3 months of
imatinib treatment, the types and grades of emerging adverse events were similar
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