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Dear all,
I would like to know your opinion on how the carcinogenicity of lovastatin
in rodents is to be extrapolated to humans. Some authors claim it should be
based on the AUC comparison rather than on dose per unit of body weight.
However if we assume that the proportion of hepatic extraction of lovastatin
in rodents is much higher than in humans would it therefore be assumed that
blood levels are not more relevant compared to the dose applied,
particularly since the principle target organs for carcinogenicity of
lovastatin seem to be liver and stomach.
Thanks for your reply ,
Marko Boh, MD
Ljubljana, Slovenia
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Marko,
You asked:
> I would like to know your opinion on how the carcinogenicity of lovastatin
> in rodents is to be extrapolated to humans. Some authors claim it should be
> based on the AUC comparison rather than on dose per unit of body weight.
> However if we assume that the proportion of hepatic extraction of lovastatin
> in rodents is much higher than in humans would it therefore be assumed that
> blood levels are not more relevant compared to the dose applied,
> particularly since the principle target organs for carcinogenicity of
> lovastatin seem to be liver and stomach.
Since you already seem to posses rodent and human PK data, if you know
the relative tissue sensitivities of liver and stomach tissues in
rodents and humans, you have the basis for a good model of human
carcinogenicity, based on rodent data. If you want to assume a 1:1
relative tissue sensitivity, you also can base an estimate on PK data
alone. Otherwise, most U.S. assessors would start with an estimate
based on body weight
to the 0.75 power (physiological time). I think that U.S. FDA
(Pharmaceutical) is using the 0.7 power of body weight for crude
estimates right now.
For a more detailed explanation, please see D.M. Byrd and C.R. Cothern,
Introduction to Risk Analysis: A Systematic Approach to Science-Based
Decision Making. [ISBN: 0-86587-696-7, Hardcover, 433 pages, 2000,
Government Institutes, Rockville, MD, $99.00 (US)] (Go to
http://www.govinst.com/pubscatalog/products/696.html.)
Dan
Daniel M. Byrd III, Ph.D., D.A.B.T.
Deputy Director
Life Sciences Research Office
9650 Rockville Pike
Bethesda, MD 20814-3998
byrdd.at.lsro.faseb.org email
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)