DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1740 In colon cancer patients, colonic perforation occurs infrequently during
bevacizumab treatment but increases in frequency in patients
with intact primary colonic tumors, peritoneal carcinomatosis, peptic
ulcer disease, chemotherapy-associated colitis, diverticulitis, or
prior abdominal radiation treatment (Gressett and Shah, 2009). The
rate of colon perforation is <1% in breast and lung cancer patients
receiving the antibody.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Sunitinib. Sunitinib (SUTENT) competitively inhibits the
binding of ATP to the tyrosine kinase domain on the
VEGF receptor-2, a mechanism it shares with sorafenib
(see “Sorafenib”). Sunitinib also inhibits other protein
tyrosine kinases (FLT3, PDGFR-α, PDGFR-β, RET,
CSF-1R, and c-KIT) at concentrations of 5-100 nM
(Fabian et al., 2005).
Sunitinib has activity in metastatic renal-cell cancer,
producing a higher response rate (31%) and a
longer progression-free survival than any other
approved anti-angiogenic drug (Motzer et al., 2007).
Sunitinib also is approved for treatment of advanced
renal-cell carcinoma and GIST that have developed
resistance to imatinib as a consequence of c-KIT mutations
(Heinrich et al., 2008). Specific c-KIT mutations
correlate with response to sunitinib. For example,
patients with c-KIT exon 9 mutations have a response
rate of 37%, whereas patients with c-KIT exon 11 mutations
have only a 5% response rate.
F
H 3 C
NH
N
H
O
CH 3
N CH 3
N
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CH 3
Pharmacokinetics and Dosing. Sunitinib is administered orally in
doses of 50 mg once a day. The typical cycle of sunitinib is 4 weeks
on treatment followed by 2 weeks off treatment. The dosage and
schedule of sunitinib can be increased or decreased according to toxicity
(hypertension, fatigue). Dosages <25 mg/day typically are ineffective.
Sunitinib is metabolized by CYP3A4 to produce an active
metabolite, SU12662, the t 1/2
of which is 80-110 hours; steady-state
levels of the metabolite are reached after ~2 weeks of repeated
administration of the parent drug. Further metabolism results in the
formation of inactive products. The pharmacokinetics of sunitinib
are not affected by food intake.
Toxicity. The main toxicities of bevacizumab are shared by all antiangiogenic
inhibitors, including sunitinib and sorafenib. Specifically,
patients taking sunitinib can experience bleeding, hypertension, proteinuria,
and, uncommonly, arterial thromboembolic events and
intestinal perforation. However, because sunitinib is a multi-targeted
O
SUNITINIB
tyrosine kinase inhibitor, it has a broader side-effect profile than
bevacizumab.
Fatigue, the most common side effect of sunitinib, affects
50-70% of patients and may be disabling. Hypothyroidism occurs
in 40-60% of patients. Bone marrow suppression and diarrhea also
are common side effects; severe neutropenia (neutrophils <1000/mL)
develop in 10% of patients. Less common side effects include congestive
heart failure (usually in association with hypertension) and
hand-foot syndrome. To monitor for these side effects, it is essential
to check blood counts and thyroid function at regular intervals.
Periodic echocardiograms also are recommended.
Sorafenib. Sorafenib (NEXAVAR), like sunitinib, targets
multiple protein tyrosine kinases (VEGFR1, VEGFR2,
VEGFR3, PDGFR-β, c-KIT, FLT-3, and b-RAF) and
inhibits their catalytic activities at concentrations of 20-
90 nM (Fabian et al., 2005).
Cl
O
F
N N
F H H
F
Absorption, Distribution, and Elimination. Sorafenib, an oral
medication, is given in daily doses of 400 mg twice a day. Patients
typically begin treatment taking 200 mg once a day and increase
dosage as tolerated. Unlike sunitinib, sorafenib is given every day
without treatment breaks. Sorafenib is metabolized to inactive products
by CYP3A4 with a t 1/2
of 20-27 hours; with repeated administration,
steady-state concentrations are reached within 1 week.
Therapeutic Uses. Sorafenib is the only drug currently approved for
treatment of hepatocellular carcinoma. In these otherwise refractory
patients, sorafenib increased median survival by 3 months compared
to placebo (10.7 versus 7.9 months) (Llovet et al., 2008). The response
rate to sorafenib was low (2%), suggesting that sorafenib primarily
has a cytostatic effect. Sorafenib also is approved in metastatic renalcell
cancer, based on improvement in progression-free survival in
patients with previously treated disease (Escudier et al., 2007).
Because of its higher initial response rate, sunitinib generally is the
preferred first-line therapy in this disease.
Adverse Effects. Sorafenib patients can experience the vascular toxicities
(bleeding, hypertension, and arterial thromboembolic events)
seen with other anti-angiogenic medications. More common adverse
effects include fatigue, nausea, diarrhea, anorexia, and rash; uncommonly,
one may notice bone marrow suppression and GI perforation
(Escudier et al., 2007).
THALIDOMIDE
SORAFENIB
Among agents with anti-angiogenic activity, the
immunomodulatory analogs (IMiDs), thalidomide and
lenalidomide, have a most unusual history and a multiplicity
of biological and immunological effects. Their
O
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CH 3