Biomedical Engineering Reference
In-Depth Information
there are other differences. Nonhuman primates used in
routine studies are relatively uniform in age (generally
young), healthy, housed in a controlled environment, fed
a controlled diet, and are typically given only one drug
plus vehicle (
Weber, 2005
). Humans in clinical trials, and
even more so in patient populations, are genetically
diverse, live in varied environments, have ranges of health
and disease conditions, have varied ages, consume varied
diets, are frequently co-administered other drugs, and live
varied lifestyles. The utility of the toxicity studies is,
therefore, to identify drug-induced changes such that
adverse events can be prevented primarily through
avoidance of doses that could cause them. This requires an
understanding and prediction of human efficacious dose
such that margins of safety can be established. Identifi-
cation of promonitory toxicity biomarkers allows more
effective prevention of administering adverse doses in
clinical
excess the exposure and duration of human exposure.
Studies are robust in design. An extensive baseline dataset
is required which evaluates all organ systems and the
overall health of the animal through collection of in-life
parameters by clinical, safety pharmacology, and clinical
pathology data, post-life parameters by gross pathology,
histopathology, and organ weight data, and other specialty
procedures (
Baldrick, 2010
). Based on the anticipated or
known toxicity profile of the drug or the attributes of the
disease in the patients, additional parameters can be
added to the standard battery. These could include
detailed neurological clinical and CNS histological
assessments for drugs causing seizures, renal biomarkers
for drugs causing tubular injury, and radiographic and
morphometrics assessments for drugs causing osteoma-
lacia in bone.
Sample collection can also affect animal species selec-
tion. For example, the amount of blood collected for stan-
dard hematology and clinical chemistry evaluations can be
limited based on the size of the animal. For rodents, rats are
more amenable to collection of adequate amounts of blood
as compared to mice, and for nonrodents, dogs are more
amenable than nonhuman primates. Similarly, within the
nonhuman primate group, marmosets have size limitations
as compared to rhesus and cynomolgus monkeys. For certain
evaluations, such as neurological, cardiovascular, and
respiratory, procedures must be scientifically valid and
technically feasible to be used in a study. Collection of these
parameters had been traditionally done and validated in
stand alone rat studies, but the need for a pharmacologically
relevant animal model for large molecule development
drives incorporation of these assessments into multidose
studies. This also addresses the 3Rs in drug development by
eliminating a set of stand alone studies.
trials, by allowing detection of
the onset of
a potentially adverse event.
Preclinical Safety Package
The entire nonclinical safety package to support drug
development and clinical trials consists of multidose toxicity,
safety pharmacology, genotoxicity, developmental and
reproductive toxicology, and carcinogenicity studies. Mul-
tidose toxicity studies are designed to address the duration,
dosage, and route of administration intended for drug
administration in clinical trials. Safety pharmacology can be
separate, stand alone studies, generally done in rat for small
molecules. When the dog or nonhuman primate is the phar-
macologically relevant species (often the case for large
molecules), safety pharmacology end points for cardiovas-
cular, respiratory, and CNS assessment can be incorporated
into multidose safety studies (
Dempster, 2000; Gauvin and
Baird, 2008
). Genotoxicity and carcinogenic potential
determination are generally not done with large molecules,
except for cause, but with small molecules are done typically
in rodents using both rat and mouse. When needed to assess
carcinogenic potential of a large molecule, a pharmacologi-
cally relevant species is needed. An example of this approach
is illustrated in a study conducted in the development of
human parathyroid hormone, in which a 4.5-year study was
done in cynomolgus monkeys to evaluate bone tumor
formation (
Vahle et al., 2008
). Monkeys were given drug for
18 months, with a subgroup terminated, and remaining
monkeys kept for a 3-year observation period. No drug-
induced tumors were identified.
NONHUMAN PRIMATE MODELS OF
SAFETY ASSESSMENT
Immunogencity
Large molecules are inherently immunogenic. Findings of
immunogenicity in nonhuman primates are not necessarily
predictive of immunogenicity in humans, but must be
determined in multidose studies in order to interpret data
and determine an appropriate development plan. Immuno-
genicity resulting in generation of neutralizing, clearing,
cross-reacting, or sustaining antibodies in the nonhuman
primate have potential to affect the nonclinical develop-
ment plan by altering the pharmacokinetic and pharmaco-
dynamic (PKPD) response (
Dempster, 2000; Frings and
Cavagnaro, 2005; Green and Hartsough, 2008; Brennan
et al., 2010
). Antidrug-antibody must be measured to
determine the effect on clearance, binding, etc. Bio-
pharmaceuticals have homologous protein structure in
Parameters in Studies
For both small and large molecules, detection of toxicity
that is relevant for risk assessment is maximized by
conducting multidose studies of durations to cover in
