Principles and Practice of Pharmaceutical Medicine

(Elle) #1

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
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