A Textbook of Clinical Pharmacology and Therapeutics

DRUGSUSED INCANCERCHEMOTHERAPY 381

Mechanism of action

Imatinibis an ATP mimetic. It competitively inhibits several
tyrosine kinases, most potently BCR-ABL and platelet-derived
growth factor receptor tyrosine kinases (IC 50 s, 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:

• nausea and vomiting;


• peripheral oedema and effusions (rare);


• leukopenia;


• skin rashes;


• hepatitis.

Pharmacokinetics

Oral absorption is very good with almost 100% bioavailabilty.
Imatiniband its active N-desmethyl metabolite have a half-
life 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. anticonvul-
sants, St John’s wort, rifamycins) will lead to reduced drug
exposure. In contrast, potent inhibitors of CYP3A (e.g. keto-
conazole) can increase the imatinibAUC 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 imatinibresistance has developed. It also inhibits
the Rous sarcoma virus (v-Src) kinase.

RECEPTOR TYROSINE KINASE INHIBITORS (RTKIs)

EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) TKIs

Uses

Erlotinibandgefitinibare used as single agents (by mouth once
daily) to treat tumours (e.g. non-small cell lung cancers) which

overexpress EGFR. Erlotinibhas 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 non-

ligand-binding domain of these receptors, there is a tyrosine

kinase which phosphorylates the receptor. Erlotinibandgefi-

tinibare 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 erlotinibandgefitinib. Their

mean elimination half-lives are 36 and 41 hours, respectively.

Botherlotinibandgefitinibare 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. anticonvul-

sants, St John’s wort, rifamycins) reduces exposure to

erlotinibandgefitinib, 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.

Growth

factor

Plasma

membrane

Receptor binding

site

Tyrosine

kinase

activity

Tyrosine

kinase

inhibitors

(TKI)

Nucleus

Gene

activation Celldivision

Signal
transduction
to nucleus
Cytoplasm

−

Figure 48.8:Inhibitory effect of tyrosine kinase inhibitors

on cell proliferation. (Redrawn with permission from

Gardiner-Caldwell communications Ltd.(©1999).)