Biomedical Engineering Reference
In-Depth Information
Due to the different attributes of each type of drug, the
approaches differ in identifying and characterizing their
effects on test animals. Relevant animal species include one
rodent, usually either rat or mouse, and one large animal
species, typically either Beagle dog or nonhuman primate.
While guidances require two species for both small and
large molecules, ICH S6 provides for a case-by-case
determination of the nonclinical plan to address biotech-
nology products (large molecules) in which a pharmaco-
logically relevant species must be used for toxicity
assessments. If only one relevant species can be identified
or if evaluation of one relevant species adequately
addresses the toxic liabilities, then the two-species
requirement may be dropped. Large molecule effects are
typically extensions of pharmacological activity, making
non-target-related effects/toxicities less likely than for
small. Small molecules, which are more traditional drugs
(i.e. low molecular weight organic chemical substances) in
which toxicity is often unrelated to pharmacological
effects, are held to the two-species requirement. Even with
small molecules in which dose-limiting toxicity may have
hyperpharmacological effects (e.g. anti-hemostasis drugs),
it may be beneficial if one of the two species has low
pharmacological sensitivity, which allows exploration of
off-target effects to best determine the range of toxic
responses that are possible.
the drug, therapeutic indication, historical database, genetic
and phenotypic variability of the species, and/or breed,
source, and supply. If all things are equal, dogs are often
given preference over nonhuman primates as a default to
the less sentient species.
Exclusive to the drug metabolism profile, the advan-
tages of dogs as compared to nonhuman primates include
ease of handling, availability, interanimal genotypic and
phenotypic consistency among purpose-bred Beagle dogs,
a preference to not use nonhuman primates due to their
similarity to humans, and availability of a historical data-
base. Advantages of nonhuman primates as compared to
dogs include reduced requirement for amount of drug
(which can be difficult to synthesize in large amounts in the
early phase of development) and physiological and
anatomical similarity to humans. Although size or test
article availability alone are not adequate justifications for
selecting nonhuman primate models over other species, the
ethical concerns of the patient population must be consid-
ered, particularly if lack of drug will significantly prolong
the development of new treatments (
Smith and Trennery,
2002
). It cannot, however, be generalized that nonhuman
primates will always (or invariably) respond to drugs or
have closer pharmacological or physiological responses to
humans as compared to dogs or rodents (
Weber, 2005
).
Certain therapeutic classes of drugs are more amenable
to evaluation in dogs or swine than nonhuman primates. For
example, drugs causing alteration in hemostasis are best
studied in dogs, unless they are a nonrelevant species due to
lack of pharmacological effect or toxic metabolite forma-
tion. Behaviorally, monkeys may be inappropriately prone
to exaggerated toxicological manifestation of altered
hemostasis and thus overestimate the toxic liability of the
drug. This is due to trauma-induced hemorrhage from
handling, restraint, and movement in the cage (which is
three dimensional, possibly resulting in hemorrhage of the
head). Dogs will be more amenable to handling, move two
dimensionally in their cage, and can be better managed
should hemorrhage occur. Likewise, humans can be
managed to reduce the potential for trauma-induced
hemorrhage and thus behaviorally may match best with
dogs for manifestation of drug-induced effects. Additional
examples include dogs as a well-accepted and often
preferred model for evaluating the effects of oncologics and
laboratory swine models, which are preferred over
nonhuman primate models for skin safety testing.
It is difficult to determine the concordance to humans of
toxicities identified in nonhuman primates and dogs for
multiple reasons: lack of clinical data, since not all drugs
tested in animals will advance to human clinical trials;
studies in animals are designed to produce toxicity while
human clinical trials are designed to avoid toxicity; doses in
animal studies are generally higher than those in clinical
trials; and some dose-limiting adverse effects in humans
Species Selection
Many factors are addressed in selecting the large animal
species, including nonhuman primates, for both small and
large molecule development. Ethical and legal consider-
ations encourage us to consider and use the species of the
lowest physiological sensitivity that will accomplish the
scientific goal with direct application of the principles of
the 3Rs (
Russell and Burch, 1959
). A document developed
by the Association of the British Pharmaceutical Industry
in conjunction with the UK Home Office discusses their
requirement to justify the use of an Old World Primate over
a New World Primate, yet acknowledges the role that
practical considerations such as availability, ease of
procedures, blood volume, and background data play in
appropriate species selection (
Smith and Trennery, 2002
).
Species selection for small molecules is heavily weighted
towards metabolism, since they are low molecular weight
organic chemicals that as a group are metabolized by phase
I and phase II reactions primarily in the liver. Drug toxicity
of small molecules may be due to the parent drug and/or the
metabolites. Selection preference is given to species
generating a similar metabolic profile to humans. Other
criteria, however, are also factored into the animal model
selection. These include appropriateness of the species for
use in a laboratory environment under conditions of the
study, prior history and precedence with similar classes of
