usefulness as agents with a high or
low therapeutic index.
Agents with a high therapeutic
index
5-HT3 RAs
The introduction of selective 5-HT3
RAs (‘setrons’) in the early 1990s
revolutionised prevention and
management of CINV. Before their
introduction, only limited effective
options were available. 1,3
Serotonin is released by
entero-endocrine cells in the
gastrointestinal tract following
administration of cytotoxics.
5-HT3 RAs act by binding to
5-HT3 receptors. Currently, the
following 5-HT3 RAs are available
(varying according to the region):
ondansetron, granisetron,
tropisetron, dolasetron,
ramosetron, azasetron (all first
generation) and palonosetron
(second generation).
They are still considered
to be the cornerstone of
standard antiemetic therapy for
control of acute emesis with
chemotherapeutic agents with
moderate to high emetogenic
potential. Palonosetron exhibits
a unique pharmacological profile
compared with other 5-HT3 RAs,
which could offer a potential
explanation of its exceptional
clinical efficacy with respect to
other ‘setrons’, and also its activity
in delayed CINV. 1,3,10
‘Setrons’ are the most effective
antiemetics in the prophylaxis
of acute CINV, are widely used,
and continue to provide effective
management of CINV. They are
particularly important in the
pathophysiology of acute vomiting
and rarely require discontinuation
of therapy. 1,3,11–16
Cytochrome P450 enzymes
(CYP) are involved in hepatic
metabolism of 5-HT3 RAs. The
CYP isoform on which metabolism
relies most varies for the different
setrons (for example, granisetron
is predominantly metabolised via
CYP3A4, whereas tropisetron and
dolasetron are mainly metabolised
via CYP2D6). 1,3,11-16
The relation with emetic
response, 5-HT3 kinetics and
genetic polymorphisms has
been described. CYP enzyme
polymorphism might be beneficial
for conversion to an alternate
5-HT3 RA and could benefit 40–50%
of patients who did not respond to
the initial 5-HT3 RA administered. 10
First-generation 5-HT3 RAs
Ondansetron, granisetron,
tropisetron, dolasetron,
ramosetron and azasetron
belong to the first-generation
‘setrons. Despite a number of
preclinical differences between
first-generation agents, a number
of randomised, comparative trials
have failed to demonstrate any
convincing difference in efficacy or
tolerability when used at effective
doses. 11–16 The first-generation
setrons appear equally effective
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