Biomedical Engineering Reference
In-Depth Information
humans. As an example, infection of cynomolgus and rhesus
monkeywith simian immunodeficiency virus (SIV) produces
a disease similar to HIV infection and AIDS in humans, and
has been used to explore chemoprophylaxis, early treatment
and immunotherapeutic strategies for treatment of HIV.
Nonclinical development of small molecule antiviral
drugs has been reviewed (
Szczech, 1996
). Toxicity is
a major concern with antiviral drugs, since along with tar-
geting the virus, they lack specificity and affect normal
cytological processes (
Shallendra et al., 2009
). Tenofovir, an
anti-HIV reverse transcriptase inhibitor, causes renal and
bone disease in humans. Nonhuman primates were used as
the animal model for studying bone toxicity. Bone changes
of osteomalacia occurred in juvenile monkeys, but not in
other species or in mature monkeys given Tenofovir
chronically (NDA 21
organism or biological system, administration-distribution-
metabolism-excretion (ADME) studies are designed to
assess changes in the molecule itself. Rather than asking
“How does the drug affect the animal or human?,” ADME
studies ask “How does the animal affect the drug?”
ADME studies consist of administering a compound,
generally small doses of material well below the maximum
tolerated dose (MTD) and collecting biological samples,
typically blood, urine, feces, and tissue samples from
multiple organ systems. Those samples are analyzed to
determine the presence and amount of unchanged
compound and compound metabolites in the samples.
Samples are collected at multiple time points to establish
the time of peak concentration, rate of elimination, clear-
ance and elimination mechanisms, organ/system concen-
trations of material, and in some cases, the amount and type
of metabolites.
Selection of nonhuman primates for ADME studies is
most often the result of a testing program requiring the
nonhuman primate model in other phases of drug devel-
opment. The reasons for choosing a nonhuman primate
model for an ADME study would be the same as those for
choosing a nonhuman primate model for safety investiga-
tions. For instance, nonhuman primates are a highly
preferred model for safety studies of large molecule and
biological compounds (
EFPIA Briefing Paper, 2008;
Chapman et al., 2010
) due to the high degree of similarity
of cross-reactivity in those compounds between nonhuman
primate and human. In species other than nonhuman
primates, a significant number of monoclonal antibodies
have no potency at all or may be highly immunogenic and
susceptible to rapid destruction by the immune system,
rendering those species irrelevant to the testing program
(
International Conference on Harmonisation, 1997
;
Chapman et.al., 2010). Nonhuman primates are also highly
relevant models for evaluating the efficacy and safety of
compounds targeting disease conditions as diverse as
infectious disease, diabetes, and neurodegenerative disease
(
EFPIA Briefing Paper, 2004
). Due to their size, avail-
ability, and the wealth of historical data and investigator
experience, the most commonly used laboratory primate
model is the cynomolgus monkey.
Colonies of nonhuman primates are often maintained
for the primary purpose of AME (Absorptions, Metabo-
lism, Excretion) studies which lack the distribution (D) data
derived from postmortem tissue samples. These colonies
can be an efficient and responsible use of nonhuman
primates, and when scientifically viable can greatly reduce
the numbers of primates used in drug metabolism investi-
gations. Animals are allowed a “wash-out” period typically
ranging from 7 to 60 days between studies, to allow elim-
ination of the majority of drug and active metabolites
before being enrolled into another study. Non-na¨ve
animals mimic the real world situation of non-na¨ve
356: Tenofovir;
Van Rompay, 2005
).
Development of the antiviral fialuridine (FIAU),
a nucleoside analog, for treatment of hepatitis B resulted in
a tragic clinical trial due to insensitivity of the nonclinical
animal models, including nonhuman primate, to predict
toxicity. In humans, FIAU caused liver failure and death
due to mitochondrial dysfunction. Routine animal species
for toxicity studies failed to detect this toxicity, as they
were insensitive to the effects of the drug. The woodchuck,
a nonstandard animal model, was found to be a better
predictor of human toxicity, demonstrating toxicity at doses
similar to that which caused liver failure in humans. This
event caused a call for changes in drug development plans,
benefit:risk assessment, use of animal and disease models,
and data assessments as exemplified by multiple letters to
the editor published in the New England Journal of
Medicine (
Letters to the Editor, 1996
). However, use of
animal models of disease for nonclinical safety assessment
remains situational and has not become routine. Further
development of other nucleoside analogs for treatment of
chronic viral diseases has continued, with applied learnings
from FIAU failed development (
McKenzie et al., 1995
).
Acyclovir is a nucleoside drug used in humans to treat
and prevent herpes virus infection. Studies were done in
a primate disease model to demonstrate drug efficacy. In
African green monkeys, acyclovir prevented development
of disease with simian varicella virus (
Soike and Gerone,
1982
). The drug was well tolerated but did cause pertur-
bations in clinical chemistry markers of renal and hepatic
injury. Nonclinical toxicity development of the drug was
done in rodent and dog, but disease model studies have
been done in nonhuman primate.
e
Administration-distribution-metabolism-
excretion Models
In contrast to classical safety and efficacy testing, where the
focus lies entirely on the impact of a drug or chemical on an
