C H A P T E R 1 4
Antineoplastic agents
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cells, it is not associated with adverse effects on normal
human cells.
Gefitinib, lapatinib, nilotinib, sorafenib, sunitinib
and temsirolimus work by inhibiting various kinases in
the cancer cell. Table 14.6 shows usual indications for
all protein tyrosine kinase inhibitors.
Gefitinib inhibits tyrosine kinases, including ones
associated with epidermal growth factor receptors. It is
usually indicated for localised, advanced or metastatic
non–small cell lung cancer (NSCLC).
Erlotinib is an oral drug that inhibits enzymes asso
ciated with epidermal growth factor. It is approved for
the treatment of non–small cell lung cancer and for
first-line treatment of pancreatic cancer when used in
combination with gemcitabine.
Bortezomib blocks a large protein complex that is
necessary for maintaining cell homeostasis, leading
to cell death. It must be given IV and is approved for
the treatment of mantle cell lymphoma and multiple
myeloma.
Pharmacokinetics
Imatinib is slowly absorbed from the GI tract, reaching
peak levels in 2 to 4 hours. It is extensively metabolised
in the liver, with a half-life of 18 and then 40 hours.
Gefitinib is slowly absorbed from the GI tract, reaching
peak levels in 3 to 7 hours. It is metabolised in the liver
with a half-life of 48 hours. Lapatinib, given orally, is
absorbed from the GI tract, reaching peak levels in 1 to
1.5 hours. Lapatinib is metabolised in the liver, with
a half-life of 24 hours. Nilotinib, given orally, reaches
peak levels in 3 hours after GI absorption. Most of the
drug is excreted unchanged in the stool with a half-life
of 17 hours. Sorafenib is well absorbed from the GI tract
after oral administration, reaching peak levels in 1 to
2 hours. Most of the drug is excreted unchanged in the
stool with a half-life of 24 to 48 hours. Sunitinib, given
orally, is slowly absorbed from the GI tract, reaching
peak levels in 6 to 12 hours. After metabolism in the
liver, it has a half-life of 40 to 60 hours and then 80 to
110 hours for its active metabolite. Temsirolimus, only
available for IV use, reaches peak levels at the end of
the infusion. It is metabolised in the liver and primarily
excreted in the faeces with a half-life of 17 hours and
then 55 hours for its active metabolite. Erlotinib is well
absorbed orally from the GI tract, reaching peak levels
in 4 hours. It is metabolised in the liver with a half-life
of 36 hours. Bortezomib, given IV, reaches peak effects
at the end of the infusion. It is metabolised in the liver
and has a half-life of 40 to 193 hours.
Contraindications and cautions
All of these drugs are in either pregnancy category C
or pregnancy category D (see Chapter 1). Women
of childbearing age should be advised to use barrier
contraceptives while taking these drugs. They can enter
breast milk, and should be used during breastfeeding
only if the benefits to the mother clearly outweigh the
risks to the baby. With imatinib, caution should be used
in people with known hepatic dysfunction. Nilotinib
is contraindicated with individuals who have or are at
risk for prolonged QT intervals (hypokalaemia, hypo
magnesaemia or taking another drug that prolongs the
QT interval) because it prolongs the QT interval, and
sudden deaths could occur. These drugs should not be
given to anyone who has a history of hypersensitivity to
any component of the drug being given.
Adverse effects
The adverse effects associated with imatinib include GI
upset, muscle cramps, heart failure, fluid retention and
skin rash. The severe bone marrow suppression, alopecia
and severe GI effects associated with more traditional
antineoplastic therapy do not occur. Gefitinib has been
associated with potentially severe interstitial lung disease
and various eye symptoms. Nilotinib causes prolonged
QT intervals and can impair liver and kidney function.
Lapatinib causes diarrhoea and can cause liver impair
ment and alter heart function. Erlotinib and bortezomib
are associated with cardiovascular events and pulmo
nary toxicity. Bortezomib has also been associated with
peripheral neuropathy and liver and kidney impairment.
Prototype summary: Imatinib
Indications:
Treatment of adults with CML who are
in blast crisis, accelerated phase, or chronic phase
after failure with interferon-alpha therapy. It has
since also been approved for use in the treatment
of people with CD117-positive unresectable or
metastatic GIST.
Actions:
Tyrosine kinase inhibitor that selectively
inhibits the Bcr-Abl tyrosine kinase created by the
Philadelphia chromosome abnormality in CML
and certain tumour cells present in GIST; blocking
this enzyme inhibits proliferation and induces cell
division.
Pharmacokinetics:
Route
Onset
Peak
Oral
Slow
2–4 hours
T
1/2
:
18 to 40 hours; metabolised in the liver and
excreted in the faeces.
Adverse effects:
Nausea, vomiting, bone marrow
suppression, heart failure, headache, dizziness,
oedema, rash.
