Biomedical Engineering Reference
In-Depth Information
dose has been proposed to provide clinical benefit with acceptably low risk of
adverse events [
47
] . Based on preclinical data [
75
] and a phase I study [
76
] , a target
plasma concentration of 50 ng/ml (parent drug
plus
metabolite SU12662) was
defined for sunitinib, even though no formal TDM study has, to the best of our
knowledge, been initiated yet for this latter drug.
Houk et al. [
47
] have shown that increased exposure to sunitinib is associated
with increased risk of adverse effects generally mild to moderate in severity. Faivre
et al. [
76
] have found dose-limiting toxicities at plasma concentrations of sunitinib
plus
SU12662 higher than 100 ng/ml.
2.5.5
Sorafenib
Pharmacokinetic Variability
Sorafenib pharmacokinetics shows a large interpatient variability [
49,
57
] . The
large interpatient variability is supposed to be the result of slow dissolution of the
drug in the gastrointestinal tract and of the existence of an entero-hepatic circula-
tion [
51
] .
Concentration-Effect Relationship
No information on sorafenib concentration-toxicity relationships is available at
present. Again, the absence of any PK-PD data does not preclude any interest for a
formal TDM for sorafenib.
A study has shown in patients with metastatic RCC and hepatocarcinoma, given
the standard regimen of sorafenib (800 mg daily), that toxicity occurrence may be
related to high plasma sorafenib exposure [
77
]. However, an upper plasma level was
not determined.
2.5.6
Lapatinib
Pharmacokinetic Variability
Lapatinib variability is large (68 %) and not significantly reduced by the coad-
ministration of food (52 %) [
45,
57
]. M. Ratain and E. Cohen [
78
] have sug-
gested that a lower dose of lapatinib could be administered if taken with food, to
take advantage of the increased absorption of lapatinib in the presence of high fat
meals, or if taken with grapefruit juice, a known CYP3A inhibitor, which should
result in an overall reduction in treatment cost. However, they strongly recom-
mended that this approach should not be done without a formal pharmacokinetic
assessment.
