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Forum,
Can anyone provide a formula of how to convert mouse dose to human dose?
Best regards,
Avi Gordon
Regulatory and Clinical Affairs Manager
BiondVax Pharmaceuticals Ltd.
Science Park, Building No. 14,
Rehovot 76326, Israel
Telephone: +972-8-9302529
gordon.-a-.biondvax.com
www.BiondVax.com
[You might look in the archives for 'first dose in man'. There isn't
a simple answer to this question. - db]
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Avi:
For conversion of animal doses to human equivalent doses, a FDA
guideline
could be useful for you: Estimating the Maximum Safe Starting Dose in
Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers
[HTML]
or [PDF] Final 7/21/2005
Nelida Mondelo
Gador SA
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Avi:
Table 1 on page 7 of the FDA guidance
http://www.fda.gov/cder/guidance/5541fnl.pdf provide a table that might
work as a starting point Human equivalent dose (mg/Kg) = mouse dose
(mg/kg)*0.08 or mouse dose (mg/Kg)/12.3
Other epical formulae people use is Rat dose is 6X mouse is 8x the human
dose. These assumptions were based on BSA scaling. When you are
starting first time in human studies you will resort to cohort type of
studies with a starting dose of 1/10th of the intended target dose for
safety reasons.
Hope this information is of some help and I want to know other experts
agree or agree to disagree.
Cheers!
Prasad
Prasad NV Tata, Ph.D., FCP
Manager-Pharmacokinetics
Mallinckrodt, Inc.
675 McDonnell Blvd.
Saint Louis, MO 63134
Tel: (314) 654-5325
Fax: (314) 654-9325
e-mail: prasad.tata.-a-.tycohealthcare.com
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This a very useful article.
J Clin Pharmacol. 2003 Jul;43(7):692-7.
Selection of the first-time dose in humans: comparison of different
approaches
based on interspecies scaling of clearance.
Mahmood I, Green MD, Fisher JE.
Murad
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Dear Prasad,
Lots of thanks for the info. Our product is an influenza vaccine
administered IM. I guess it is quite different from oral drug. How
would you
calculate the human dose then.
Best regards,
Avi Gordon
Regulatory and Clinical Affairs Manager
BiondVax Pharmaceuticals Ltd.
Science Park, Building No. 14,
Rehovot 76326, Israel
Telephone: +972-8-9302529
gordon.at.biondvax.com
www.BiondVax.com
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The following message was posted to: PharmPK
Avi,
I agree that vaccines are unlike classic pharmacologically active
molecules
so pharmacological toxicity is not an issue. The dose of antigen and
amounts
of inert excipients are so small that their volume or mass is virtually
immaterial.
The main safety issue is ensuring a safe immunological response.
Apart from
anaphylaxis ( minimised by reducing the number of complex and antigenic
molecules to a minimum and especially avoiding excipients like
Cremophor EL)
the only clues you will have are from animal studies. Evidence from
primates
would be the more likely to be representative of a putative human
response
than a dog or rodent. That is in both he qualitative and quantitative
senses.
It is essential to provide a good assay for the response you seek,
otherwise
you are shooting in the dark. In other words you do a PD study from
study 1
and not just safety. You then choose a desired response as your
uppermost
dose target that is based on a scientific rationale, either from your
primate studies or know human responses to standard vaccines in
humans for
existing influenza strains.
I expect you will need repeated doses to obtain the maximum response,
so you
need to factor that in. I would keep it simple in the first study and
repeat
the same dose 2 or 3 times starting very low indeed. How low I
cannot say
without seeing some data on predicted antigenicity
I would guess that the dose of your antigen will be so small that
classic
pharmacokinetics will not apply. By that I mean for example that
there are
target plasma concentrations.
Andrew Sutton
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This may not be applicable to your agent, but I will post this link
anyway. This is the drug dose calculator on the CDER website
(calculations are based on relative body surface areas, and obviously
this may not predict your actual results, but it is a good place to
start):
http://www.fda.gov/cder/cancer/animalframe.htm
Cheers,
Kevin Foley
Kevin P. Foley, Ph.D.
Associate Director, In Vivo Pharmacology
Synta Pharmaceuticals Corp.
45 Hartwell Avenue
Lexington, MA 02421 USA
Tel: 781-541-7231
Fax: 781-274-8228
E-mail: kfoley.-at-.syntapharma.com
http://www.syntapharma.com
http://myprofile.cos.com/kpfoley
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The following message was posted to: PharmPK
Avi
A simple formula is:
Species 2 (mg/kg) = Species 1 (mg/kg) x (km1/km2)
Where km1 for mouse is 3
and km2 for human is 37
Ref:
Drug Toxicokinetics, Marcel Dekker (eds, Peter Welling & Felix de la
Iglesia)
regards
Brian
[Does that include any sort of safety factor? - db]
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Avi,
I hope adds positively to the opinions posted here by all the experts.
To my knowledge, interspecies scalng works well (maybe better) with
protein and peptide drugs compared to small molecules. Of course, you
can always go with mechanistic or semi-mechanistic models to
determine the contributions of various clearance processes (these may
be dictated by the antibodies forming). However, the latter process
is time-consuming and may not reflect the real differences between
species.
Below are three general references addressing these issues pertaining
to peptide drugs and antibodies. Also, the work by J. Balthasar from
SUNY-Buffalo is a good reference for PK and PD modeling of these agents.
1: Mahmood I.
Interspecies scaling of protein drugs: prediction of clearance from
animals to
humans.
J Pharm Sci. 2004 Jan;93(1):177-85.
2: Hu TM, Hayton WL.
Allometric scaling of xenobiotic clearance: uncertainty versus
universality.
AAPS PharmSci. 2001;3(4):E29.
3: Tang L, Persky AM, Hochhaus G, Meibohm B.
Pharmacokinetic aspects of biotechnology products.
J Pharm Sci. 2004 Sep;93(9):2184-204. Review.
I hope this helps.
Murad Melhem, Ph.D.
Cognigen Corporation
395 Youngs Road
Buffalo, NY
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Brian,
Do you have the Km values for other species like rat, dog, monkey
Thanks
Ananda
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Dear ananda!
The surface area of experimental animals and its corresponding dose
calculation is available in the book "Experimental pharmacology" By
MN.Ghosh. I do not know whether it is available in US. Please check
Thanks and Regards,
M.Kamaraj,M.Pharm,
Cancer biology,
Orchid Research Laboratories Ltd,
Chennai-119,INDIA
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Amanda
Km values for mouse, hamster, rat, monkey, dog, man are: 3, 4.1, 5.2,
11.5, 20, 37
regards
Brian
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