J. vet. Pharmacol. Therap. 31, 533–537, doi: 10.1111/j.1365-2885.2008.00991.x.

Comparative efficacy of maropitant and selected drugs in preventing emesis

induced by centrally or peripherally acting emetogens in dogs

H. S. SEDLACEK* Sedlacek, H. S., Ramsey, D. S., Boucher, J. F., Eagleson, J. S., Conder, G. A.,
D. S. RAMSEY* Clemence, R. G. Comparative efficacy of maropitant and selected drugs in
preventing emesis induced by centrally or peripherally acting emetogens in
J. F. BOUCHER*
dogs. J. vet. Pharmacol. Therap. 31, 533–537.
J. S. EAGLESON*
G. A. CONDER* & Maropitant (CereniaTM; a novel, selective neurokinin1 receptor antagonist),
R. G. CLEMENCE   chlorpromazine, metoclopramide and ondansetron were compared in two
randomized, placebo-controlled studies for efficacy in preventing emesis induced
*Veterinary Medicine Research & by emetogens acting centrally (apomorphine; Study 1) or peripherally (syrup of
Development, Pfizer Inc, Kalamazoo, MI, ipecac; Study 2) in dogs. In each study, ten male and ten female beagles were
USA;  Veterinary Medicine Research & treated in a five-treatment, five-period crossover design. The five treatments
Development, Pfizer Ltd, Sandwich, Kent, were 0.9% saline (0.1 mL ⁄ kg), maropitant (1 mg ⁄ kg), metoclopramide
UK
(0.5 mg ⁄ kg), or chlorpromazine (0.5 mg ⁄ kg) all administered subcutaneously,
or ondansetron (0.5 mg ⁄ kg) administered intravenously. One hour posttreat-
ment dogs were challenged with apomorphine at 0.1 mg ⁄ kg intravenously
(Study 1) or syrup of ipecac at 0.5 mL ⁄ kg orally (Study 2). Following emetogen
challenge, dogs were observed for 30 min (Study 1) or 1 h (Study 2) for emesis.
No clinical signs, other than those related to emesis, were observed. Efficacy of
maropitant in preventing emesis induced centrally by apomorphine was not
different (P > 0.05) from metoclopramide or chlorpromazine but was superior
(P < 0.0001) to ondansetron. Efficacy of maropitant in preventing emesis
induced by syrup of ipecac was not different (P > 0.05) from ondansetron but
was superior (P £ 0.0102) to metoclopramide or chlorpromazine. Maropitant
was effective (P < 0.0001 relative to control) in preventing vomiting caused by
stimulation of either central or peripheral emetic pathways, whereas the other
drugs examined prevented vomiting caused by central (metoclopramide and
chlorpromazine; P < 0.0001) or peripheral (ondansetron; P < 0.0001) stim-
ulation but not both.
(Paper received 12 January 2008; accepted for publication 29 May 2008)
George A. Conder, Pfizer Animal Health, 7000 Portage Rd., Kalamazoo, MI 49001
USA. E-mail: george.a.conder@pfizer.com

INTRODUCTION itant (CereniaTM), a novel, highly specific NK1 receptor antag-

It is generally believed that neurokinin1 (NK1) receptors within
the nucleus tractus solitarus, the area postrema and the dorsal
motor vagal nucleus play a major role in emesis (Gardner et al.,
1996; Sanger, 2004), and it has been established that the
neuropeptide Substance P, a potent agonist of the NK1 receptor,
is a key neurotransmitter in the pathophysiology of emesis
(Gardner et al., 1995, 1996; Watson et al., 1995; Diemunsch
et al., 1999; Diemunsch & Grélot, 2000). A number of studies
have demonstrated that NK1 receptor antagonists have broad-
spectrum antiemetic activity to both centrally and peripherally
acting emetogens (e.g. Gardner et al., 1995, 1996; Watson et al.,
1995; Diemunsch et al., 1999). Two studies reported herein
were conducted to demonstrate that the citrate salt of marop-
onist, can provide broad-spectrum antiemetic efficacy in dogs
against both centrally. (Study 1, apomorphine) and peripherally
(Study 2, syrup of ipecac) acting emetogens and to compare this
activity to that of three drugs (chlorpromazine, metoclopramide
and ondansetron) approved for humans, which are commonly
used to control emesis in dogs.
MATERIALS AND METHODS
Two studies were conducted in dogs according to international
standards for good clinical practice (VICH GL9, 2001). Both stud-
ies were run to a common protocol, except that different emeto-
gens were used. The centrally acting emetogen apomorphine

 2008 The Authors. Journal compilation  2008 Blackwell Publishing Ltd 533
534 H. S. Sedlacek et al.

was used in Study 1, while the peripherally acting emetogen
syrup of ipecac was used in Study 2.
Animals
In each study, 10 male and 10 female beagles were selected from
a pool of 24 healthy dogs. Dogs selected for study weighed 8.9–
13.5 kg (Study 1) or 8.3–14.5 kg (Study 2) and were 7–
44 months (Study 1) or 6–45 months (Study 2) of age. Each dog
was individually housed and randomly allocated to cage and
treatment sequence by gender. Dogs had access to food and
water ad libitum, except on treatment days when they were
fasted for a minimum of 2 h prior to treatments.
Treatments
Each study utilized a five-period, five-treatment crossover design
for each sex. The five treatments included 0.9% saline (placebo;
American Pharmaceutical Partners, Inc., Schaumburg, IL, USA)
at 0.1 mL ⁄ kg, maropitant (Pfizer, NY, USA) at 1 mg ⁄ kg,
metoclopramide (Mayne, Paramus, NJ, USA) at 0.5 mg ⁄ kg, or
chlorpromazine (Baxter, Deerfield, IL, USA) at 0.5 mg ⁄ kg with
each administered subcutaneously, and ondansetron (Glaxo-
SmithKline, Research Triangle Park, NC, USA) at 0.5 mg ⁄ kg
administered intravenously. The dose of saline was selected to
parallel the volume injected per kilogram of animal weight for
maropitant to deliver a 1 mg ⁄ kg dose. Metoclopramide was
administered at the European maximum registered label dose for
dogs of 1 mg ⁄ kg (Bayer S.P.A., Milan, Italy). Chlorpromazine
was administered off-label at an effective antiemetic dose
reported in the literature (Fossum & Hedlund, 1997). Ondanse-
tron was also administered off-label at a dose routinely used by
veterinary oncologists to control chemotherapy-induced nausea
and vomiting (Hall, 2002). Subcutaneous treatments were
administered in the loose skin over the shoulder blades, while
intravenous treatments were administered in the front leg. For
all treatments, drugs were administered on the dog’s right side
for the first, third and last treatment and on the left side for the
second and fourth treatment. The same 10 treatment sequences
were used for both males and females in both studies and these
10 treatment sequences (detailed in Table 1) were randomly
assigned to the 10 animals of each sex in each study. The 10
treatment sequences were chosen so that each treatment
followed every other treatment equally throughout the experi-
ment. This condition allows for estimation of both treatment
effects and carryover effects. The washout period was expected to
eliminate any carryover effect; however, this design allowed for
estimation of the treatment effects even in the presence of a
carryover effect. For each treatment, dogs were challenged
approximately 1 h posttreatment with an emetogen, either
apomorphine (Meds for Vets, Sandy, UT, USA) at 0.1 mg ⁄ kg
intravenously (Study 1) or syrup of ipecac (Humco, Texarkana,
TX, USA) at 0.5 mL ⁄ kg orally (Study 2). The doses and routes of
administration were based on the literature for apomorphine
(Scherkle et al., 1990; Yoshida et al., 1995) and for syrup of
ipecac (Schwartz et al., 1994). There was a 7-day washout
period between treatments, i.e., 28 days were required for a dog
to receive all five treatments.
To ensure the welfare of the study animals, a rescue
antiemetic was administered to any dog which experienced five
or more emetic events during a posttreatment observation
period. The rescue antiemetic was metoclopramide administered
at a dose of 0.5 mg ⁄ kg subcutaneously per the standard
operating procedure for the research facility. Animals that
received the rescue antiemetic continued with the next antie-
metic treatment and emetogen challenge per treatment sequence
after a 7-day washout.
Data collection
Immediately after emetogen administration, a trained observer,
masked to treatment, counted and recorded emetic events for
each dog. Dogs challenged with apomorphine were observed
for emesis for 30 min following challenge, while those
challenged with syrup of ipecac were observed for 1 h. An
emetic event was defined as active retching or vomiting.
Production of excessive saliva, which passively flowed from the
mouth (drooling), was not recorded as an emetic event. The
observation period following apomorphine (30 min) or syrup
of ipecac (1 h) challenge were based on times reported in the
literature (apomorphine – Yoshida et al., 1995; Yoshikawa
et al., 2001 and syrup of ipecac – Schwartz et al., 1994). Dogs
were observed throughout the study for any abnormal clinical
signs.

Table 1. Treatment sequence used in Studies

Treatment
1 and 2 for both male and female dogs. Each
Sequence Period 1 Period 2 Period 3 Period 4 Period 5
treatment appears twice in each period and
1 Saline Maropitant Chlorpromazine Metoclopramide Ondansetron each treatment follows all other treatments
2 Maropitant Metoclopramide Saline Ondansetron Chlorpromazine twice throughout the design
3 Metoclopramide Ondansetron Maropitant Chlorpromazine Saline
4 Ondansetron Chlorpromazine Metoclopramide Saline Maropitant
5 Chlorpromazine Saline Ondansetron Maropitant Metoclopramide
6 Ondansetron Metoclopramide Chlorpromazine Maropitant Saline
7 Chlorpromazine Ondansetron Saline Metoclopramide Maropitant
8 Saline Chlorpromazine Maropitant Ondansetron Metoclopramide
9 Maropitant Saline Metoclopramide Chlorpromazine Ondansetron
10 Metoclopramide Maropitant Ondansetron Saline Chlorpromazine

 2008 The Authors. Journal compilation  2008 Blackwell Publishing Ltd

 Prevention of emesis by maropitant compared to other drugs 535

Statistical analysis Table 2. Summary of emetic events for dogs challenged with apomor-
phine intravenously at 1 mg ⁄ kg (Study 1) or syrup of ipecac orally at
For each study, the primary efficacy variable was number of 0.5 mL ⁄ kg (Study 2) approximately 1 h following treatment with
emetic events observed. The (number of emetic events + 1) for selected antiemetics
each animal on each treatment was analyzed using a generalized Apomorphine challenge Syrup of ipecac challenge
linear model with a log link and Poisson error allowing for over-
dispersion (SAS Institute, 1999). The model included the fixed Least squares Range Least squares Range
effects of sex, period, treatment and carryover with the random mean number** of mean number** of
of emetic events emetic of emetic events emetic
effects of animal within sex and residual error. The 10 treatment
Antiemetic* (95% CI***) events (95% CI***) events
sequences were chosen so that each treatment followed every
other treatment equally throughout each study. A term for Saline (Placebo) 1.45a (1.06, 1.92) 0–3 1.64a (1.12, 2.28) 0–5
carryover was created for which the value was the treatment Chlorpromazine 0.18b (0, 0.49) 0–2 2.22a (1.64, 2.92) 0–5
Maropitant 0.03b (0, 0.32) 0–1 0.10b (0, 0.54) 0–1
given the previous period (with period 1 assigned a dummy
Metoclopramide 0b 0 0.92a (0.49, 1.48) 0–6
treatment). The carryover term was balanced such that each
Ondansetron 1.67a (1.25, 2.17) 0–6 0b 0
treatment had equal representation. This term was tested in the
statistical model and dropped from the final analysis as the *Saline (0.1 mL ⁄ kg), chlorpromazine (0.5 mg ⁄ kg), maropitant
carryover effect was not significant (P > 0.05) in both studies. (0.1 mg ⁄ kg) and metoclopramide (0.5 mg ⁄ kg) were administered sub-
Because of model convergence issues a treatment was not cutaneously and ondansetron (0.5 mg ⁄ kg) was administered intrave-
nously. **Values in a column with an a or b superscript do not differ
included in the model if no emetic events were recorded
significicantly (P > 0.05) from saline or maropitant, respectively.
following that treatment, which was the case for metoclopra- ***CI = confidence interval
mide in Study 1 (apomorphine challenge) and for ondansetron in
Study 2 (syrup of ipecac challenge). The treatment effect was The least squares mean number of emetic events for dogs given
significant (P £ 0.05) in both studies, therefore emetic events maropitant did not differ significantly (P > 0.05) from those of
for maropitant, metoclopramide, chlorpromazine, and ondanse- dogs treated with metoclopramide or chlorpromazine, but emetic
tron were each compared with saline (placebo) for significance events were significantly reduced (P < 0.0001) for maropitant
(P £ 0.05) and emetic events for metoclopramide, chlorprom- relative to ondansetron treatment (0.03 vs. 1.67 emetic events,
azine and ondansetron were each compared with maropitant for respectively). Apomorphine challenge failed to elicit emesis
significance (P £ 0.05). For comparisons with a treatment following saline treatment on four of 20 occasions. No dog
group which was excluded from the model because of no emetic required rescue therapy after challenge with apomorphine.
events (metoclopramide in Study 1 and ondansetron in Study 2), In Study 2 where dogs were challenged with syrup of ipecac
the least squares mean number of emetic events of the approximately 1 h after treatment in each period of the
comparator group (saline or maropitant) was compared with crossover, there was a significant reduction (P < 0.0001) in
zero for significance (P £ 0.05). Use of the least squares (model least squares mean number of emetic events experienced by the
generated) means rather than arithmetic means or medians dogs following treatment with maropitant or ondansetron (0.1
provides for calculation of an appropriate confidence interval and 0 emetic events, respectively) relative to saline-treated
associated with each least squares mean. animals (1.64 emetic events), however there was no significant
reduction (P > 0.05) with metoclopramide or chlorpromazine
treatments (0.92 or 2.22 emetic events, respectively). The least
squares mean number of emetic events for dogs given marop-
RESULTS
itant did not differ significantly (P > 0.05) from those of dogs
treated with ondansetron, but emetic events were significantly
Safety
reduced (P £ 0.0102) for maropitant relative to metoclopra-
Aside from emesis resulting from emetogen challenge, there were mide or chlorpromazine treatment (0.1 vs. 0.92 or 2.22 emetic
no abnormal clinical signs or adverse events in either study. events, respectively). Syrup of ipecac challenge failed to elicit
emesis following saline treatment on five of 20 occasions. Five
dogs received rescue therapy after challenge with syrup of ipecac
Efficacy
(one saline-treated, two metoclopramide-treated, and two chlor-
Table 2 summarizes emetic events from Studies 1 and 2 by promazine-treated dogs).
treatment. In Study 1 where dogs were challenged with apomor- Figure 1 shows the comparative effectiveness of the four
phine approximately 1 h after treatment in each period of the antiemetics tested, in preventing apomorphine (centrally acting;
crossover, there was a significant reduction (P < 0.0001) in least Study 1) or syrup of ipecac (peripherally acting; Study 2) induced
squares mean number of emetic events experienced by the dogs emesis. As the figure shows, only maropitant was effective in
following treatment with maropitant, metoclopramide, or chlor- controlling emesis resulting from both central or peripheral
promazine (0.03, 0, or 0.18 emetic events, respectively) relative to challenge.
saline-treated animals (1.45 emetic events), while there was no The effect of gender was significant (P £ 0.0271) in both
reduction following ondansetron treatment (1.67 emetic events). studies irrespective of treatment, with least squares mean

 2008 The Authors. Journal compilation  2008 Blackwell Publishing Ltd

536 H. S. Sedlacek et al.

3.0 demonstrated by the data reported herein which shows that

LSMean number of emetic events

Apomorphine maropitant is effective against both centrally (apomorphine) and

2.5 Ipecac peripherally (syrup of ipecac) acting emetogens. Not only did
+
maropitant exhibit an ability to significantly (P < 0.0001)
2.0
+ reduce emesis relative to a saline negative control for both
+
+ emetogens, but it was also the only antiemetic examined which
1.5
was effective against both centrally and peripherally acting
1.0 + emetogens (Table 2 and Fig. 1). Metoclopramide and chlor-
promazine were effective in reducing apomorphine-induced but
0.5 not syrup of ipecac-induced emesis and ondansetron effectively
* reduced syrup of ipecac-induced but not apomorphine-induced
0.0 * * * * emesis (Table 2 and Fig. 1). Further, against each emetogen,
Saline

Maropitant

Ondansetron

Chlorpromazine
Metoclopramide

maropitant was as effective (not significantly different; P > 0.05)

or more effective (significantly better; P < 0.0102) than any of
the other antiemetics examined (Table 2 and Fig. 1).
With the recent approval of maropitant (CereniaTM) in both
the United States and Europe for the treatment and prevention of
Fig. 1. Comparative efficacy of selected antiemetics in preventing emesis acute emesis of various etiologies and vomiting associated with
in dogs following challenge with apomorphine (centrally acting; Study 1) motion sickness in dogs, veterinarians in these regions have for
or syrup of ipecac (peripherally acting; Study 2) challenge approximately the first time (with the exception of some European countries) a
1 h after treatment. Treatments were 0.9% saline (0.1 mL ⁄ kg), marop-
drug approved specifically for these indications in dogs. The
itant (1 mg ⁄ kg), metoclopramide (0.5 mg ⁄ kg), or chlorpromazine
broad-spectrum utility of maropitant should provide veterinar-
(0.5 mg ⁄ kg) administered subcutaneously or ondansetron (0.5 mg ⁄ kg)
administered intravenously. Error bars represent the upper 95% ians with a valuable new tool with which to manage emesis in
confidence interval (CI) (note that due to a log transformation of data veterinary patients irrespective of cause (except intestinal
prior to analysis, CI on the mean are not likely to be symmetrical). An *or obstruction or toxin ingestion) and it should provide an
+ indicates a significant (P < 0.05) difference from saline or maropitant, opportunity to revise treatment and support strategies, previ-
respectively. All statistical comparisons are within type of challenge. ously dependent on etiology, to minimize the impact of emesis in
sick dogs.
numbers of emetic events of 0.95 and 0.45 (Study 1) or 1.47 and
0.72 (Study 2) for females and males, respectively. Although the
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