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The following message was posted to: PharmPK
Dear all,
I am working with one of the standard drug. I know the mouse LD50
dose from the literature, Oral(176mg/kg), IV(149mg/kg). The drug
is highly water soluble and bioavailability is approx. 100%. I
have done single oral study at 120mg/kg, the animals were fine.
My doubt is i want to take up IV study at 90mg/kg, is it OK?, the
dose which i am planning to take is not too far from reported IV
LD50 (149mg/kg), is there any formula or rational to calculate the
maximum dose that can be administered safely to the animals
without any side effects or death.
Thanks in advance for your inputs.
B.L.Suresh
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The following message was posted to: PharmPK
Dear all,
I am working with one of the standard drug. I know the mouse LD50
dose from the literature, Oral(176mg/kg), IV(149mg/kg). The drug
is highly water soluble and bioavailability is approx. 100%. I
have done single oral study at 120mg/kg, the animals were fine.
My doubt is i want to take up IV study at 90mg/kg, is it OK?, the
dose which i am planning to take is not too far from reported IV
LD50 (149mg/kg), is there any formula or rational to calculate the
maximum dose that can be administered safely to the animals
without any side effects or death.
Thanks in advance for your inputs.
B.L.Suresh
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The following message was posted to: PharmPK
I am assuming that you are asking about doses to the mouse but you do
not say so. My rule-of-thumb, when I used to work in the pre-clinical
area, was to use a bolus IV dose of 1/10th the oral dose. With the use
of an infusion pump (assuming the bioavailability is 100%) you could
mimic the oral profile and, therefore, administer the same dose. What
surprises me a little bit is that 120 mg/kg was OK but the LD50 was
only 176 mg/kg. I would have expected the NOEL to be lower than 120
mg/kg - on the other hand, I don't now anything about the drug you are
studying.
regards
Brian
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The following message was posted to: PharmPK
Dear Suresh:
Usually the oral lethality curves are wider than the i.v. ones which are
much more steeper. The other data is that you found no toxicity with the
oral 120 mg/kg dose which is 0.166 logarithmic units apart from the 176
mg/kg oral LD50. Then, as the 149 mg/kg LD50 is 0.219 logarithmic units
apart from the 90 mg/kg dose -and if the i.v. curve is really steeper
than
the oral one- you should not find toxicity with the 90 mg/kg i.v. dose.
All
this rationale assumes that your animals will respond exactly in the
same
range of doses than the bibliography reports.
If it were possible for you, the best thing to do would be to perform an
i.v. lethality curve in order to find out how steep is the curve and how
your animals respond. Then, if the curve is fairly steep, you should not
find any effect with the 90 mg/kg dose. You simply graph the results as
% of
lethality vs log dose (ideally the % of lethality should be graphed in a
probabilistic scale, Litchfield & Wilkinson), then you can find out if
you
expect any death at that dose. Also, if you do not want to employ a lot
of
animals you could try just with four animals per dose (2 male and 2
female)
in order to have an idea.
Hope this helps,
Silvia
[I not sure that a LD 50% study (or lethality study?) would be
justified (speaking as an ex-member of our local IACUC). Can you start
somewhat little lower. Do you know what to expect re toxicity and dose
up to the start of signs of toxicity...start of signs i.e. not death? -
db]
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