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Dear All,
I would like to listen to some comments on the emetic response in
beagle dogs, during preclinical PK evaluation. The compound has good
pharmacological properties, adequate rodent PK properties and
requires further investigation.
However, generates severe emetic response in dog when given as a
suspension in Tween.
Are there some ways to handle this issue, some other approaches, by
which this response can be minimised.
Would look forward to hearing some suggestions.
Nikhil.
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In fact dogs do not support Tween neither per IV (severe tremors are
oftenly observed) nor per Os (severe emetic events and potential
tremors).
I suggest you set up smarter formulations to dose in dogs.
I have a strong experience in setting up formulations for preclinical
studies from my work at Aventis, Parke-Davis and Pfizer and I now
offer consulting activities in drug discovery.
So if you need support to design a smart formulation strategy
depending on both the kind of preclinical studies and the animal
species to be dosed, do not hesitate to contact me (see contact
information below).
Best regards,
Frederic Doc
ACRITER - drug discovery consulting
URL : www.acriter-consulting.com
e-mail : fdoc.aaa.acriter-consulting.com
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Nikhil,
This is the just the nature of the species. For PK studies,
sometimes 0.25
mg/kg acepromazine IM 0.5 h before administration helps. This is not
acceptable for future toxicity studies. In my experience for certain
classes of compounds this is going to happen and there is not much
you can
do about it other than change species. However, one should not consider
rejecting a compound that causes emesis, even severe in dogs. OTOH,
if you
see it in two species....
Dale
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Nikhil,
Administration of Tween 80 to dogs has resulted in the following
reactions:
Tween 80 4% 1 ml/kg IM Facial swelling, generalised
hyperaemia, polydipsia,
vocalisation. 1/32 dogs sacrificed in extremis
4% 0.5 ml/kg (3 doses)IM Findings as above.
No dogs sacrificed
1% IV 3/12 dogs sacrificed.
Swollen limbs, hyperaemia,
scleral effects, bright red mucous membranes, emesis,
recumbency. Liver, kidney lung and skin pathology
Suggest you avoid Tween.
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Nikhil
It appears that the emesis that you are seeing is following oral
dosing to dogs?? Tween does not cause emesis in dogs when used at
levels of 1-2% of the total formulation if administered orally. The
question to ask is when is the emesis occurring?? If it is at time
periods less than Tmax, local GI irritation by the compound seems to
be the problem. If it is much later than Tmax, a systemic effect
(probably CNS related) is the more likely cause.
Although dogs are very sensitive to local GI irritation and
subsequent emesis (more so than other higher species), this finding
(which appears to be compound related) translates reasonably well
into the clinic. Lowering the dose may help or diluting the
concentrations in the GI tract by dosing with food or immediately
following food may also help (provided food does not mess up your
absorption/bioavailability).
If the effect is due to a systemic exposure, then you are dealing
with a safety margin issue and you may be forced to lower your safety
margin (and tighten your therapeutic index). Even with an
unmanageable local effect you will have to work with safety margins
or change your route of administration.
Good Luck with your project and hope this helps
Anup
Anup Zutshi Ph.D.
Pfizer Inc
Pharmacokinetics, Dynamics and Metabolism
T-3O/318E
700 Chesterfield Parkway (W)
Chesterfield, MO 63017
(314) 274-8349
Anup.Zutshi.-at-.Pfizer.com
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Colleagues,
In his reply to Nikhil Anup wrote that gastric irritation could be the
mechanism of the emesis in dogs and that it can be ameliorated by
diluting
the drug or dosing with food. The University of Surrey in the UK has a
practical, non-invasive, bio-impedance method for gastric emptying and
simultaneous motility for investigating gastric emptying and
contractility
in animals and man. Nausea is both a precursor of emesis in man and
accompanied by gastric delay, so it can be used as a predictor of
vomiting
potential at low doses. That allows the exploration of lower doses
that may
well be effective and so to establish the therapeutic ratio as Anup has
suggested. In man the system is very sensitive. Witness a fourfold
increase
in emptying half times after a small (0.09 mg/kg) iv dose of morphine in
healthy volunteers. (Murphy DB et al, 1997, Opioid-induced Delay in
Gastric
Emptying, Anesthesiology, 87, 765-770).
Andrew Sutton.
Andrew Sutton, MBBS, MD(London), FFA
Guildford Clinical Pharmacology Ltd.
The Technology Centre, Occam Road
Guildford, Surrey, UK. GU2 7YG
Tel: +44 (0)1483 455375. Direct: 688303
URL: www.gcpl.co.uk
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