A Textbook of Clinical Pharmacology and Therapeutics

Plasma
membrane
Signal
transduction
to nucleus
Cytoplasm
Mechanism of action
Growth
factor
Imatinib is an ATP mimetic. It competitively inhibits several
tyrosine kinases, most potently BCR-ABL and platelet-derived
growth factor receptor tyrosine kinases (IC 50s, 100–300 nM) and a
mutated c-KIT. In CML, the BCR-ABL fusion protein is pivotal in
driving cellular replication and proliferation pathways. In GIST,
it is c-KIT that is overactive and drives proliferation. Inhibition
of these tyrosine kinases causes the cell to undergo apoptosis.
Adverse effects
These include the following:
Nucleus
Gene
activation
• nausea and vomiting;
• peripheral oedema and effusions (rare);
• leukopenia;
• skin rashes;
• hepatitis.
Receptor binding
site
Tyrosine
kinase
activity
Pharmacokinetics
Oral absorption is very good with almost 100% bioavailabilty.
Imatinib and its active N-desmethyl metabolite have a halflife
of 18 and 40 hours, respectively. It is inactivated by hepatic
CYP3A. The kinetics do not change with chronic dosing and
little drug appears unchanged in the urine.
Drug interactions
Concurrent use of drugs that induce CYP3A (e.g. anticonvulsants,
St John’s wort, rifamycins) will lead to reduced drug
exposure. In contrast, potent inhibitors of CYP3A (e.g. ketoconazole)
can increase the imatinib AUC by 40%.
Dasatinib (available in the USA) is another TKI. It is active
against most imatinib-resistant BCR-ABL kinases and may be
useful after imatinib resistance has developed. It also inhibits
the Rous sarcoma virus (v-Src) kinase.
RECEPTOR TYROSINE KINASE INHIBITORS (RTKIs)
EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) TKIs
Uses
Erlotinib and gefitinib are used as single agents (by mouth once
daily) to treat tumours (e.g. non-small cell lung cancers) which
−
Cell
division
Tyrosine
kinase
inhibitors
(TKI)
DRUGS USED IN CANCER CHEMOTHERAPY 381
Figure 48.8: Inhibitory effect of tyrosine kinase inhibitors
on cell proliferation. (Redrawn with permission from
Gardiner-Caldwell communications Ltd.(©1999).)
overexpress EGFR. Erlotinib has the best evidence of survival
benefit for advanced lung cancer patients. Tumours that bear a
mutation in the EGFR receptor which makes it constitutively
activated may be more susceptible, but how to select patients
who will benefit from treatment is still under investigation.
Mechanism of action
The EGFR receptor belongs to a family of four receptors
expressed/overexpressed on certain tumours. In the nonligand-binding
domain of these receptors, there is a tyrosine
kinase which phosphorylates the receptor. Erlotinib and gefitinib
are ATP mimetics and are competitive inhibitors of the
EGFR-1 tyrosine kinases. Inhibition of this tyrosine kinase
blocks EGFR signal transduction and causes the cell to
undergo apoptosis.
Adverse effects
These include the following:
• diarrhoea;
• acneiform skin rash;
• nausea and anorexia;
• hepatitis;
• pneumonitis;
• decreased cardiac contractility (EF).
Pharmacokinetics
Oral absorption is very good for erlotinib and gefitinib. Their
mean elimination half-lives are 36 and 41 hours, respectively.
Both erlotinib and gefitinib are metabolized by hepatic CYP3A
to metabolites with little or no tyrosine kinase inhibiting activity.
Drug interactions
Concurrent use of drugs that induce CYP3A (e.g. anticonvulsants,
St John’s wort, rifamycins) reduces exposure to
erlotinib and gefitinib, whereas use of inhibitors of CYP3A
have the opposite effect.
Multi-EGFR TKIs and irreversible EGFR TKIs are in late
phase clinical development, so new agents in this group are
anticipated.