Animals are not perfect models for humans but there is, currently, no alternative means of assessing the effects of product administration on the whole organism.
USE OF ANIMALS TO PREDICT HUMAN
TOXICITIES
Animals
are not perfect models for humans but there is, currently, no alternative means
of assessing the effects of product administration on the whole organism. Some
non-clinical safety assessments are performed using in vitro methods, for example potential for genotox-icity is partly
assessed using a bacterial cell muta-genicity assay and a chromosomal
aberration assay in mammalian cells. Many of the parameters examined in safety
pharmacology, metabolism and toxicity studies are, however, functions of the
whole animal.
The
use of animals in safety studies is necessi-tated by regulatory requirements
and assumes that animal toxicities are generally predictive of hazard to
humans. This assumption is the result of experience, which indicates that
toxicology studies in laboratory animals yield data that are predictive of
human toxi-cities. It is, however, essential to review this funda-mental
assumption for both scientific and political reasons. Only if we can be
confident that animal models yield data that is predictive of human toxicities
can we be confident that safety assessments are useful and justify the test
systems. The consequences of poor prediction include inappropriate use of
animals, unforeseen toxicities and unwarranted restrictions on potentially
useful drugs, which may limit their thera-peutic benefits.
The
concordance of the toxicities of pharmaceuti-cals in animals and humans is,
then, fundamental to the use of animal study data in safety assessments prior
to human administration. Commercial confiden-tiality limits the availability of
data on this subject, but there are some literature reports on the subject. In
a survey of 139 drugs approved in Japan from 1987 to 1991 (Igarashi, 1994),
animal toxicity data were drawn from 468 repeated dose studies, mainly in rats
and dogs but with a few in mice and monkeys. Forty-three percent of clinical
toxicities from 69 marketed drugs were not predicted from animal studies. The
best predictability was for cardiovascular events and the poorest was for skin
and hypersensitivity reactions. More recently, a multinational survey of 12
pharma-ceutical companies was reported, in which data from 150 compounds that
produced human toxicity events were reviewed, and the human toxicities related
to the non-clinical findings (Olson et al.,
2000). When toxi-cities in rodent and non-rodent species were examined
together, there was a concordance rate of 71% with the human toxicities. The
concordance rate for non-rodent species was 63%, whilst for rodents alone it
was 43%. Ninety four percent of these concordances were first observed in
studies of 1-month duration or less. The human toxicities that showed the
highest concordance with non-clinical data were haematolog-ical,
gastrointestinal and cardiovascular effects. The lowest concordance rate was in
cutaneous toxicities.
The
two reviews both indicate that cardiovascu-lar toxicities observed in clinical
studies are likely to have been observed first in animals and that cutaneous
toxicities also seem to be less apparent in non-clinical than in clinical
studies. On the surface, it appears that the Japanese data from marketed drugs
and the multinational data from products in clinical trials had similar rates
of concordance between non-clinical and clinical findings. The Japanese data
indicated that 43% of toxicities in marketed drugs could not have been
predicted from the non-clinical results, whilst the rate of concordance for
drugs where human toxicities were observed during development was 71%. Presum-ably
29% of toxicities could not have been predicted from the non-clinical data.
Caution should be exer-cised in correlating these figures because a number of
those products which caused toxicities in clinical trials will not have reached
the market. In addition, some rare toxicities may not be detected in clinical
trials and may only be revealed when the product is on the market and used by a
much larger and more mixed population. Olson et al. cited reviews of clin-ical toxicity resulting in withdrawal
from marketing; only 4 of 24 cases and 6 of 114 cases could have been predicted
from animals. This poor rate of prediction is considered to be unsurprising
because late-onset toxic effects are usually idiosyncratic and therefore
inher-ently of low incidence, are not dose related and are not related to the
drug’s pharmacology.
It
may be impossible to improve the rate of predic-tion of rare and idiosyncratic
human toxicities from non-clinical studies, but care should be taken to
maximise the rate of prediction for those toxicities related to the metabolism
of the test material or to its pharmacological actions. The choice of animal
model is very important in this; inter-species differences in metabolism
influence the metabolite profile, the route and rate of clearance of
xenobiotics, whilst differ-ences in the specificity and/or distribution of
receptors give rise to differences in pharmacological responses to a given
pharmaceutical. In order to maximise the usefulness of the non-clinical data in
safety assess-ment, the species used for toxicity testing should be chosen
based on their similarity to humans with regard to pharmacokinetic profile.
Additionally, the chosen species should be responsive to the primary
pharma-codynamic effect of the substance wherever possible, and in some cases
studies in disease models may be warranted (EMEA, 2000b).
Apart
from species differences, there are several other factors that may increase the
rate of incorrect predic-tions of toxicity when moving from animals to man.
These include differences in the way the toxicity is observed and recorded
(eliciting verbal accounts of symptoms is not possible in animals), the
presence or absence of concomitant medication, pharmacokinetic and metabolic
differences, age (animals are young and humans may be old), state of health
(animals are free from disease), the small numbers and homogeneity of the
animals studied compared with the heterogeneity of the humans, dose
differences, housing and nutrition (optimal in animal studies) as well as
timing differences.
Overall,
the published data suggest that between one-half and two-thirds of
pharmaceutical toxicities in humans can be predicted from non-clinical data,
thus supporting the use of in vivo
toxicology data in assessing the potential for human toxicity. Recently,
however, the importance of choosing the most appro-priate animal models and
tests and of applying their results in the most appropriate way during safety
assessments has come into sharp focus. This has been highlighted by the severe,
life-threatening side effects suffered by six healthy volunteers in a Phase I,
first-in-human, clinical study in the UK. The medic-inal product administered,
TGN1412, is a mono-clonal antibody that was being developed as an
immunomodulator and is one of a new generation of medicinal products which are
being developed as technology allows the identification and targeting of more
complex biological systems.
Repeated dose testing of the antibody had been performed in
cynomolgus monkeys and it had been well tolerated by the animals following
repeated dosing at doses of up to 50 mg/kg/week for 4 consecutive weeks. This
dose level was therefore taken as the no observed adverse effect level (NOAEL)
and was used as the basis for calculating the starting dose for the clinical
study. The method of calculation followed draft guidelines that are frequently
applied to inves-tigational products (FDA, 2002; see also following section)
whose mechanisms of action and secondary effects may be better understood than
those of the new generation products such as TGN1412. Having applied safety
factors and allometric correction factors to scale between the monkey and
humans, the human starting dose was selected at 500 times less than the monkey
NOAEL. The devastating effects caused in the volunteer subjects clearly
demonstrates that use of the no observed adverse effect level obtained from the
repeated dose cynomolgus monkey study did not provide a sufficient margin of
safety for human dosing of this product.
Examination
of this case and of the wider implications for safety assessment of medicinal
products – with specific reference to (1) biological molecules with novel
mechanisms of action; (2) new agents with a highly species-specific action; (3)
new drugs directed towards immune system targets – is ongoing (Duff et al., 2006). Further comment here is
therefore inappropriate.
The
investigations into this case seem likely to result in new guidance on the
safety testing and assess-ment of such products. Whatever the outcome, the case
has highlighted the fact that, whilst standard toxi-cological testing has had a
good record in predicting the safety of new chemical entities and biologicals
whose activities and targets are well understood, new strategies are required
to assess the newer genera-tion of products that are designed to modulate more
complex biological systems. For more conventional products, however, current
toxicology testing strate-gies and safety assessments remain useful although it
is pertinent to examine their role and success in predicting human toxicities.
This chapter therefore focuses on these types of assessment.
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