Biomedical Engineering Reference
In-Depth Information
Concentration-Effect Relationship
Burris et al. [
53
] showed in patients with metastatic solid tumors treated with
lapatinib at doses ranging from 500 to 1,600 mg once daily that clinical responses
were generally associated with doses in the middle of the range examined.
Clinical response was more often associated with doses of 900-1,200 mg daily.
However, due to the limited response data, it was not possible to adequately char-
acterize the relationship between clinical response and drug exposure, which
would be a prerequisite before assessing the potential role of TDM in lapatinib
dosage individualization.
Finally, relationships between lapatinib plasma concentration and clinical toxic-
ity have not been yet formally studied.
2.5.7
Miscellaneous TKIs
Pharmacokinetic Variability
Very large variations have been demonstrated for gefitinib exposures and for the
recent TKI axitinib (evaluated for metastatic melanoma, renal cell and thyroid
cancer, and NSCLC), with variation in drug exposure ranging between 113 %
and 39-94 % for gefitinib and axitinib, respectively [
48
]. In that context, an assay
for phenotyping patients' CYP3A activity has been proposed for predicting
gefitinib systemic exposure and helping at drug dosage selection [
79
] . Erlotinib
interpatient pharmacokinetic variability is also important (60 %) and, as yet,
unexplained [
52
] .
Information on the clinical pharmacokinetics is also available of the recently
approved TKIs. Vandatenib pharmacokinetics, studied in healthy volunteers and
patients [
80,
81
] was found to be both influenced by patient's renal function and
vulnerable to drug-drug interactions [
82,
83
]. An important pharmacokinetic vari-
ability is noticeable in the mean steady state PK profiles published for verumafenib
(formerly PLX4032) [
27
] .
Several new TKIs are in advanced stage of clinical development, including bosu-
tinib [
84
] and bafetinib [
85
], the third-generation TKIs against imatinib-, nilotinib-,
and dasatinib-resistant CML; the multi-targeted kinase inhibitor pazopanib,
approved for advanced or metastatic RCC [
86
]; and neratinib with antitumor activity
in HER2-positive breast cancer. Bosutinib, pazopanib and neratinib are all sub-
strates of the CYP3A enzymatic system, and their plasma exposure is increased
when coadministered with potent CYP3A inhibitors [
86-
88
] , potentially requiring
dose adjustment for neratinib [
87
] .
Finally, pharmacokinetics and metabolic studies are also available for TKIs at
various stages of clinical development, including vatalanib [
89-
91
] , cediranib
[
92-
94
] , and motesanib [
95
] .
