Biomedical Engineering Reference
In-Depth Information
because of the grade 2 pleural effusion (Table 8.3). The frequency of
pleural effusions was lower than the occurrence of pleural effusions
with the dasatinib 70 mg twice daily dosage. Gastrointestinal and
other bleeding events occurred in 5% of patients in each group. The
median change in the QTc interval from baseline was 3.0 msec in
the dasatinib group and 8.2 msec in the imatinib group. The overall
rates of discontinuation of therapy because of toxic effects of the
drug were 5% with the dasatinib group and 4% with the imatinib
group [54].
The follow-up period in the study is not long enough to draw the
meaningful conclusion of differences in the survival benefit between
the treatment groups. The early data of higher rates of CCyR and MMR
with dasatinib and early evidence of reduced rates of progression
to more aggressive phases of CML suggest that the upfront use of
dasatinib therapy may improve the long-term outcome in patients
with treatment naïve CML-CP.
8.5.2.2
Nilotinib
Nilotinib (AMN107, Novartis) is an, orally active, aminopyrimidine-
derivative tyrosine kinase inhibitor that is more potent against
CML cells
than is imatinib. Like imatinib, nilotinib functions
through competitive inhibition at the ATP-binding site of BCR-ABL,
leading to the inhibition of tyrosine phosphorylation of proteins that
are involved in the intracellular signal transduction that BCR-ABL
mediates. Nilotinib has a higher binding affinity and selectivity for
the ABL kinase than imatinib. Nilotinib is 10 to 50 times more potent
than imatinib in inhibiting the proliferation and autophosphorylation
of wild-type BCR-ABL cell lines and most of the BCR-ABL mutants,
except the T315I mutant [49, 55,56].
In the phase II study nilotinib 400 mg twice daily (800 mg/
daily was administered to all patients with CML-CP following
imatinib resistance or intolerance based on safety, tolerability and
pharmacokinetic data from the phase 1 study [57]. At 6 months
of treatment rates of MCyR and CCyR rates were 48% and 31%,
respectively. Among patients who achieved a MCyR 96% continued
treatment without progression or death for at least 6 months. Eleven
percent of patients discontinued treatment because of disease
progression [58].
A baseline mutation analysis was available on 182 patients in
the study. After 6 months of therapy, MCyR was achieved in 42%
in vitro
