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Dear All,
In talking to toxicologists I have heard many times that dosing on a
mg/m**2 basis is equivalent in both animals and man if bioavailability
is the same. I keep telling them they they are insane to believe this.
When I probe as to a source for this statement I get none. Does
anyone know of any book where this is actually stated or any literature
reference that actually espouses this type of thinking?
Thanks,
pete
Peter L. Bonate, PhD
Director, Pharmacokinetics
ILEX Oncology, Inc
4545 Horizon Hill Blvd
San Antonio, TX 78229
email: pbonate.-at-.ilexonc.com
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Maybe this experience is helpful, although it is interspecies
extrapolation rather than animal to man (and vice versa):- In our
studies on platinum PK (cisplatin)in birds (Aust Vet J 2000;78:406-411)
we used a published allometric scaling algorithm to adjust the dose
commonly used in Pt chemotherapy in dogs (70 mg/m2) to the "equivalent"
dose in birds (6.4 mg/kg). However, significant nephrotoxicity occurred
at this dose and which only disappeared when the bird dose was reduced
to 1 mg/kg, highlighting the need to obtain PK data from Pt dosing in
the species of interest rather than by extrapolation from other sources.
Cheers,
BC
Bruce CHARLES, PhD
Associate Professor and Director
Australian Centre for Paediatric Pharmacokinetics
School of Pharmacy, The University of Queensland
QLD 4072 Australia
[University Provider Number: 00025B]
http://www.uq.edu.au/pharmacy/charles.html
http://www.mater.org.au/pharm/acpp/index.htm
B.Charles.-a-.pharmacy.uq.edu.au
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Peter:
You might want to refer to "Interspecies Scaling, Biological Design and
Neoteny" by Harold Boxenbaum and R.W. DSouza Advances in Drug Research
1990,
19, 139-191
Hope this would be a starting point,
Prasad Tata
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Pete,
I have this info while I clean my desk and may not be complete.
Species Factor: mouse=3, rat=6, dog=20, monkey=12, human=37,
rabbit=12 and horse=39. and the formula is (mg/m^2)/x=(mg/kg)x(The
ink is faint and it may not be correct). Can someone tells me that
is it the scaling factor between species?
Bill Tong
Memorial Sloan Kettering Cancer Center
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Peter
One book that contains this sort of information is:
Drug Toxicokinetics, ed Peter Welling & Felix de la Iglesia, Marcel
Dekker, Inc.
regards
Brian
Brian E. Davies
Clinical Director, PDMP
Hoffmann-La Roche, Nutley, NJ
brian.davies.at.roche.com
(973) 235 2053
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Hey Pete
An often cited paper is Freirich et al. (1966) Quantitative comparison
of
toxicity of anticancer agents in mouse, rat, hamster, dog monkey, and
man.
Cancer Chemother. Rep. 50:219. The authors showed that toxicity in man
could be predicted on the basis of dose on a mg/m2 basis.
While there is no strict rule, we toxicologists would like to believe
(and
hope with the start of a clinical trial) that we can contribute to
predictions of human toxicity based on our animal data.
Jeffrey L. Larson, Ph.D.
Director of Toxicology and Pharmacokinetics
Tanox, Inc.
4888 Loop Central Drive
Houston, TX 77081-2225
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I believe that this may be the original reference. (These are some
well-respected authors to be calling insane.) This concept is also
stated in many cancer textbooks. The point is that normalizing to
surface area is a better starting point than normalizing to weight. No
one is claiming that the behavior of individual agents does not differ
significantly from this generalization.
Cancer Chemother Rep 1966 May;50(4):219-44
Quantitative comparison of toxicity of anticancer agents in mouse, rat,
hamster,
dog, monkey, and man.
Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE.
PMID: 4957125 [PubMed - indexed for MEDLINE]
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"Newman, Edward" wrote:
>
> PharmPK - Discussions about Pharmacokinetics
> Pharmacodynamics and related topics
>
> I believe that this may be the original reference. (These are some
> well-respected authors to be calling insane.) This concept is also
> stated in many cancer textbooks. The point is that normalizing to
> surface area is a better starting point than normalizing to weight.
I dont know whether the cited authors are insane but certainly the
surface area method has been abandoned by allometric biologists for a
long time (Peters 1983). I accept that the surface area method is a
reasonable *approximation* (Holford 1996) to a theoretically
justifiable and experimentally supported allometric model (West et al.
1997,1999) -- but why use surface area when weight alone does a better
job to predict how body function (e.g. drug clearance) or structure
(e.g. drug volume of distribution) varies with size?
Note that surface area is nearly always an allometric prediction based
on weight and height (e.g. du Bois & du Bois 1916) rather than direct
measurement.
An online tutorial on allometric scaling and why surface area does not
cut the mustard can be found here:
http://www.anaesthetist.com/physiol/basics/scaling/Kleiber.htm
It is just not true to say "normalizing to surface area is a better
starting point than normalizing to weight" unless you qualify it by
saying that weight normalization is done using the naive per kg model
that has been recognized to be inadequate for centuries!
Isn't it time for toxicologists and cancer textbook authors to catch up
with the scientific literature and learn from other areas of biology?
du Bois D, du Bois EF. A formula to estimate the approximate surface
area if height and weight be known. Archives of Internal Medicine
1916;17:861-871
Peters R. The ecological implications of body size. Cambridge:
Cambridge University Press; 1983
Holford NHG. A size standard for pharmacokinetics. Clinical
Pharmacokinetics 1996;30:329-332
West GB, Brown JH, Enquist BJ. A general model for the origin of
allometric scaling laws in biology. Science 1997;276:122-26
West GB, Brown JH, Enquist BJ. The fourth dimension of life: fractal
geometry and allometric scaling of organisms. Science
1999;284(5420):1677-9
--
Nick Holford, Divn Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.-a-.auckland.ac.nz
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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Bill,
I'm not sure if I correctly understand what you are asking, but the
numbers
you list appear to be the factors for converting a dose from mg/kg to
mg/m^2
in the respective species. They come from the original 1966 paper in
Cancer
Chemotherapy by Freireich et al. Although I don't think the paper
mentioned
rabbits or horses.
Jim Peggins
James O. Peggins, Ph.D.
Toxicology & Pharmacology Branch
Developmental Therapeutics Program, DCTD
National Cancer Institute
Bethesda, Maryland 20892
pegginsj.-a-.mail.nih.gov
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"Newman, Edward"wrote:
> "... The point is that normalizing to
> surface area is a better starting point than normalizing to weight.
> ..">>
Toxicologists, using physiologically based pharmacokinetic models
realized long time ago, that allometric scaling to 3/4 power of body
weight (BW^0.75) works best for most physiological and pharmacokinetic
parameters.
Best wishes.
Janusz Z. Byczkowski, Ph.D.,D.Sc.,D.A.B.T.
Consultant
212 N. Central Ave.
Fairborn, OH 45324
e-mail januszb.at.AOL.com
homepage: http://members.aol.com/JanuszB/index.html
JZB Consulting web site: http://members.aol.com/JanuszB/consult.htm
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Dear colleagues,
The present discussion on allometric scaling is both interesting and
vivid.
The website with the Kleiber Rules is a very practical and useful
starting
point for the topic (thank you, Nick!).
I would like to make three additional comments:
1) Janusz Z. Byczkowski wrote:
> Toxicologists, using physiologically based pharmacokinetic models
> realized long time ago, that allometric scaling to 3/4 power of body
> weight (BW^0.75) works best for most physiological and pharmacokinetic
> parameters.
The word 'most' is discutable. The power of 3/4 refers to most
parameters
expressed in 'amount/time', e.g. clearances and metabolic processes. In
general, volumes (e.g. volume of distribution) are approximately
proportional to weight. Consequently, 'rates' are scaled by a power of
0.25,
and time values by a power of -0.25.
2) The arguments against body surface area (usually an allometric
estimate
based on weight and height, as pointed out by Nick Holford) may be
convincing in allometric scaling, in favor of scaling to 3/4 power of
body
weight (I did not yet read the listed references, so I cannot make my
own
decision). But I am not sure whether the '3/4 power of body weight' is
also
superior over 'body surface area' in scaling between individuals of the
species man, e.g. for individualisation of doses for extremely large or
heavy persons, or for children, infants and newborns.
As an example: consider a small fat person of 150 cm and 100 kg, and a
tall
person of 200 cm and 100 kg. According to the weight rules, the
clearance of
both persons would be estimated the same, so the same maintenance dose
(mg/day) should be given, i.e. (100/70)^0.75 = 1.31 times the normal
dose
(70kg). Based on body surface area, the area of the small fat person is
1.92
m2, and the dose would be 1.07 time the normal dose (1.8 m2). For the
tall
person, the surface area is 2.37 m2, and the dose 1.32 time the normal
dose.
I would be interested to hear convincing arguments which dosing advise
is
the best for the small fat person.
3) Even the best allometric scaling cannot be expected to take into
account
the large interspecies differences with respect to hepatic enzyme
activity
of the most important metabolic enzymes. So, the allometric scaling is
not
more than a 'best guess' for the metabolic clearance of a species not
yet
investigated. The same applies, probably to a lesser extent, to the
interindividual variability in metabolic clearance. A 'best guess' is
better
than a blind guess, but not a formal rule.
best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
Email: j.h.proost.-at-.farm.rug.nl
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)