Principles and Practice of Pharmaceutical Medicine

and cats. This method could be expected to save
time and money in the drug discovery process by
enabling us to do the following:

1. 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).


2. 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