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I am new to the field of allometry and am having some troubles with
one particular prediction that I am working on. For this one
compound, we have IV CL(mL/min) and Vss(L/kg) respectively as
follows: Mouse (0.0555, 0.778), Rat (0.65, 0.548), Dog (20.28, 1.1).
When I plot log Cl vs log BW, I get very nice straight lines for both
Cl and Vss with equations being : log CL = 0.9488 log BW + 0.3106 and
log Vss = 1.069 log BW - 0.837 with R-squared values of 0.999 for
both CL and Vss. However, after this for concentration projections,
when I convert the concentrations and times to plot Complex Dedrick
plots (I am using Complex Dedrick since exponent of Vss is greater
than 1) , instead of overlapping plots , I get almost 3 parallel
plots with C0 for Dog about 10-fold higher than rat and C0-rat being
10 fold higher than C0-mouse (on a log scale). When the plots are
overlapping, then concentration vs time projections calculations are
straight forward but when the plots are parallel with about 10-fold
difference in their C0 values , then how does one proceed to do these
projections? Does this mean allometry fails to predict conc vs time
(for a specified dose & BW of another species in question/
prediction). Do we need to get data from another species to make any
For Dedrick plots I am plotting C/(Dose/BW d) vs Time/ BW d-b where
d = 1.069 and b = 0.9488 from above equations.
For another compound in the same series we got v.similar data but for
that we also had monkey data and surprisingly, the monkey and rat
plots were exactly superimposible and the dog had 10-fold higher C0
(but parallel plot) and mouse had 10-fold lower C0 (again parallel
plot). So what does this tell us?
Thanks so much for any advice/input on this. Shall be eagerly looking
forward to it !
Tonika Bohnert, Ph.D
Biogen Idec Inc.,
15 Cambridge Center
Cambridge, MA 02142
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The following message was posted to: PharmPK
It is essentially impossible with such small amounts of data to
estimate allometric model exponents with any hope they might be
unbiased and precise. The theoretically correct values for the
exponent of Clearance of 0.75 and for volume is 1.0.
What are you trying to do with your allometric predictions?
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
email:n.holford.at.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
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Although there are many allmetric methods, why not to examine
the molecular properties of your compound first? The studied
molecular descriptors are simple.
Jolivette LJ, Ward KW 2005. Extrapolation of human pharmacokinetic
parameters from rat, dog, and monkey data: Molecular properties
associated with extrapolative success or failure. J Pharm Sci 94(7):
Evans CA, Jolivette LJ, Nagilla R, Ward KW 2006. Extrapolation of
preclinical pharmacokinetics and molecular feature analysis of
"discovery-like" molecules to predict human pharmacokinetics. Drug
Metab Dispos 34(7):1255-1265.
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