Buat perbedaan dari masing-masing obat antikanker golongan imunoterapi

(imatinib) ditinjau dari mekanisme kerja, farmakokinetika (ADME), indikasi, efek

samping/toksisitas obat, dosis, kontraindikasi/perhatian interaksi, bentuk sediaan)
Imatinib merupakan inhibitor dari domain tirosin kinase dari onkoprotein BCR-ABL
dan mencegah fosforilasi substrat kinase oleh ATP. Obat ini diindikasikan untuk
pengobatan leukemia myelogenous kronis (CML), suatu hematopoietik gangguan sel
induk yang ditandai oleh translokasi kromosomal Philadelphia..berpotensi majemuk
Ditandai dengan t (09:22) Philadelphia translokasi kromosom. Ini hasil translokasi
dalam protein fusi Bcr-Abl, agen penyebab di CML, dan hadir pada sampai dengan
95% dari pasien dengan penyakit ini. Agen ini juga menghambat reseptor tirosin
kinase lainnya untuk reseptor platelet-derived growth factor (PDGFR) dan c-kit.
Lisan Imatinib diserap dengan baik, dan dimetabolisme di hati, dengan
penghapusan metabolit terjadi terutama di feses melalui ekskresi bilier. Agen ini
telah disetujui untuk digunakan sebagai terapi lini pertama dalam fase kronis CML
dalam krisis blast, dan sebagai terapi lini kedua untuk tahap kronis CML yang telah
berkembang di sebelum terapi interferon-alpha. Imatinib JUGA efektif dalam
pengobatan tumor stroma gastrointestinal mengekspresikan c-kit tyrosine kinase.
Efek samping utama yang tercantum dalam Tabel 54-5zxas
Imatinib is an inhibitor of the tyrosine kinase domain of the Bcr-Abl oncoprotein and
prevents phosphorylation of the kinase substrate by ATP. It is indicated for the
treatment of chronic myelogenous leukemia (CML), a pluripotent hematopoietic
stem cell disorder characterized by the t(9:22) Philadelphia chromosomal
translocation. This translocation results in the Bcr-Abl fusion protein, the causative
agent in CML, and is present in up to 95% of patients with this disease. This agent
also inhibits other receptor tyrosine kinases for platelet-derived growth factor
receptor (PDGFR), and c-kit. Imatinib is well absorbed orally, and it is metabolized in
the liver, with elimination of metabolites occurring mainly in feces via biliary
excretion. This agent is approved for use as first-line therapy in chronic phase CML,
in blast crisis, and as second-line therapy for chronic phase CML that has progressed
on prior interferon-alfa therapy. Imatinib is also effective in the treatment of
gastrointestinal stromal tumors expressing the c-kit tyrosine kinase. The main
adverse effects are listed in Table 545zxas
Sumber: katzung page 936, 937

Miscellaneous Targeted Agents

Imatinib and Dasatinib. Imatinib mesylate is a selective inhibitor of the tyrosine
kinase activity of BCR-ABL fusion gene, the product of the Philadelphia chromosome.
84 The Philadelphia chro- mosome is the hallmark finding of chronic myeloid
leukemia (CML) and is a translocation of genetic material between chromosome 9
and 22. Imatinib mesylate binds to the kinase binding site of the BCR-ABL gene,
competitively blocking access to adenosine triphosphate. This prevents tyrosine-
kinase phosphorylation of the gene and downstream activation of cellular
proliferation. 84 Imatinib mesylate also causes apoptosis or arrest of growth in
hematopoietic cells expressing BCR-ABL. An additional effect of imatinib mesylate is
its ability in blocking the tyrosine kinase activity of c-KIT (stem- cell factor receptor)
and platelet-derived growth factor receptor. 54,84 Imatinib mesylate is a standard
treatment option for newly diagnosed Philadelphia chromosome-positive (Ph+) CML
and for c-KIT (CD117)-positive gastrointestinal stromal tumors. A major advance
seen with imatinib mesylate therapy is its ability to eliminate the Philadelphia
chromosome in patients receiving therapy resulting in cytogenetic responses
(elimination of the genetic defect), thus achieving the goal of all targeted therapies;
the attack and elimination of the underlying cancer biology. Adverse effects to
imatinib mesylate are usually mild to moderate in severity. Severe fluid retention
(pleural effusion, pericardial effusion, and ascites) occurs in less than 10% of
patients taking imatinib mesylate. Patients should be monitored regularly for early
signs and symptoms of fluid retention (leg swelling, shoes no longer fitting, and
shortness of breath) and instructed to call their health care clinicians when
symptoms first develop. Additional adverse effects for imatinib mesylate include
mild or moderate superficial edema, elevation of liver enzymes, nausea, muscle
cramps, headache, and rash. 85 Rash may require early intervention as rare cases
of Stevens-Johnsons syndrome have been reported with imatinib mesylate and may
require permanent discontinuation of therapy. 85 Imatinib mesylate is metabolized
by and is an inhibitor of the CYP3A4 enzyme system and caution should be
exercised when substrates, inducers, or inhibitors of CYP3A4 are used concomitantly
with imatinib mesylate. 85 Additionally, imatinib mesylate is an inhib- itor of the
CYP2D6 and levels of CYP2D6 substrates can increase. Dasatinib is a next-
generation tyrosine kinase inhibitor that shares the same binding site on the BCR-
ABL tyrosine kinase adenosine triphosphate-binding domain with imatinib. In
contrast, dasatinib maintains clinical activity in CML and Philadelphia chro-
mosome-positive acute lymphocytic leukemia patients with muta- tions in the BCR-
ABL binding site that confer imatinib resistance. It recently received FDA-approval
for the treatment of patients with CML resistant to imatinib or other therapies.
Dasatinib also inhibits a family of tyrosine kinases called SRC kinases that are
believed to mediate cellular differentiation, proliferation, and survival; SRC kinases
have been implicated in modulating multiple oncogenic signal transduction
pathways. 84 Dasatinib has a toxicity profile similar to that of imatinib with
myelosuppression, nausea and vomiting, headache, and fluid retention being
commonly reported. Dasatinib has also been reported to cause hypocalcemia and
pleural effusions. Similar to other tyrosine kinase inhibitors, dasatinib has extensive
drugdrug interactions with agents metabolized by the CYP3A4 isoenzyme.