and cats. This method could be expected to save
time and money in the drug discovery process by
enabling us to do the following:
- Select the correct dose in an animal model of
disease. These studies are expensive and time
consuming. The selection of the wrong dose in
an animal model, especially in a model in a
larger species such as cat, could lead to invalid
results, either through toxicity (if the dose is too
high) or inactivity (if the dose is too low). - Provide confidence that the pharmacological
model will predict efficacy in humans. If a
drug is effective in therapeutic models using
different species and these animals receive
equivalent exposures (as measured by the max-
imum plasma concentration,Cmax, or area under
the plasma concentration curve, AUC), then the
clinician can choose a dose for trials with con-
fidence.
3. Eliminate unnecessary doses and plasma sam-
ples in the first trials in humans.
The discovery process for compound X, which is
efficacious in a number ofin vivomodels, is again
an illustrationof howallometric considerations can
enhance the development process. The whole brain
concentrations of this compound are in equilibrium
with plasma concentrations within 5 min after
dosing, and it is also eliminated from the brain in
equilibrium with the declining plasma concentra-
tion. We also know that compound X is80%
orally bioavailable in rats and dogs (see above)
and has linear (first-order elimination) and predict-
able pharmacokinetics in animals.
Next, this compound was tested in a model of
excitotoxicity, in which the neurotoxin malonate
was injected into the striatum of rats. A subcuta-
neousinjectionofcompoundXat9 mgkg^1 caused
an 80% reduction in the lesion activity produced by
malonate. TheCmaxplasma levels of compound X
at this dose would be about 1500 ng ml^1.
In a study using spontaneously hypertensive
rats, a dose of 12 mg kg^1 of compound X was
also neuroprotective [these rats were subjected to
2 h of focal ischemia by occlusion of the right
middle cerebral artery (MCA), followed by 22 h
of reperfusion]. With the assumption of 100%
systemic absorption, the expected plasmaCmaxat
this dose was 2000 ng ml^1. In this model, there
was a significant reduction (greater than 30%) in
cortical infarct volume, compared with saline con-
trols, when the drug was given at the time of
occlusion and at 0, 0.5, 1 and 1.5 h post-MCA
occlusion.
Using the data from the neuroprotection models
from rats, we then scaled a dose to the cat that was
Table 8.4 Equivalent surface area dosage conversion factors
Body surface Approximate human
Species Body weight (kg) area (kg m^2 ) Factor (Km) dose equivalent
Mouse 0.02 0.0067 3.0 1/12
Rat 0.100 0.0192 5.2 1/7
Dog 8.0 0.400 20 1/2
Monkey 2.5 0.217 11.5 1/3
Human 60 1.62 37 N/A
Dose in species 1 (mg kg^1 )¼dose in species 2 (mg kg^1 ).
0.40
0.00
−0.40
−0.80
−1.20
−1.60
−2.00
−2.40
−2.00−1.50−1.00−0.50 0.00 0.50 1.00 1.50 2.00
log 10 body weight (kg)
Surface area (m
2 )
Adult
Dog Child
Monkey
Rat
Mouse
Figure 8.3 Allometric relationship between body sur-
face area and species body weight on a log vs. log plot
PREDICTION FROM ANIMALS TO HUMANSIN VIVO 87