Biomedical Engineering Reference
In-Depth Information
development. As described in ICH S7A “Safety Pharma-
cology Studies for Human Pharmaceuticals" (2000), the
CNS is identified as a critical system and the effects of
compounds on this system should be evaluated prior to the
first human dose. In addition to the more standard
prescribed toxicology assessments (
International Confer-
ence on Harmonisation, 2010
), the ICH S7A prescribes
a behavioral investigation of the pharmacological effects of
novel compounds on the CNS using a core testing battery
requirement. As in other specialized safety assessment
studies, the animal model of CNS toxicity is typically an
extension of the model selected for the larger testing
program.
The similarity of nonhuman primates to humans, both
anatomically and physiologically, is well established and is
the basis of extrapolatory testing in nonhuman primates.
The literature holds numerous examples of direct correla-
tion between nonhuman primate and human brain structure
and function, in areas as diverse as cytoarchitectonic
analysis, brain structure and cognition, preserved learning,
aging, and neurotoxicity (
Zola-Morgan and Squire, 1984;
Zilles et al., 1995; Adolphs, 1999; Petrides and Pandya,
1999; Zhang et al., 2000; Burton and Guilarte, 2009
).
Although rodents are most typically used in the first tier of
neurotoxicity assessment, many compounds are either
pharmacologically inactive or are metabolized differently
in the rodent, making the rodent less appropriate for risk
assessment (
Chapman et al., 2009; International Confer-
ence on Harmonisation, 2009
). In addition, it is the high
order cognition, complex behaviors, and fine motor skills of
the nonhuman primate that make it an appropriate model
for investigating neuroactive compounds and in second tier
studies (
O'Keeffe and Lifshitz, 1989
).
The ICH guidelines call for a functional assessment of
motor activity, behavioral changes, coordination, sensory/
motor reflexes, and body temperature (ICH S7A). Primates
can be trained for participation in functional observation
batteries (FOBs) which resemble those designed for
rodents (
Gauvin and Baird, 2008
). Similarly, veterinary
neurological examinations, while not the same as those
performed in canines due to handling limitations, have
a similar focus and are designed so that motor skills,
behavior, coordination, and strength can be assessed by an
observer. With minimal animal training and the use of
restraint devices such as a primate chair, many cranial and
spinal reflex assessments are possible including palpebral,
corneal, menace, patellar, flexor, and nociception reflexes.
These assessments may be conducted as part of a well-
designed toxicity study rather than as a separate study
(
International Council on Harmonisation, 2000, 2009
).
Nonhuman primate models are increasingly important
for safety studies in pediatric drug products. The 2006
guidance issued by the FDA relating to pediatric drugs
offers recommendations for designing studies to evaluate
toxicity endpoints in intended pediatric populations
(
Guidance for Industry: Nonclinical Safety Evaluation of
Pediatric Drug Products, 2006
). Investigators are encour-
aged to consider comparative organ development between
pediatric patients and juvenile animals and other factors
when choosing an animal model. The infant and juvenile
nonhuman primate is a highly appropriate model for
a number of target organs and systems, but none more so
than the central nervous system. A wealth of research
literature, dating back to the early 1900s, supports the
applicability of neonatal and juvenile nonhuman primate
models to human pediatrics (
Schneider et al., 2006
). Test
batteries designed specifically to assess developmental
toxicity in nonhuman primate neonates have been shown
useful in assessing safety by measuring physiological state
(respiration, membrane color, temperature, muscle tone),
reflexes (grasp, palmer, righting), behavior (lipsmack,
suckling, arousal), and activity patterns (sleep, position
changes, movement) (
Golub, 1990
).
Developmental and Reproductive
Toxicology (DART)
Developmental toxicity refers to safety assessments
covering the phases from implantation until delivery and
monitoring the offspring even until the second generation
(F2). Reproductive toxicity specifically addresses aspects
of male and female fertility parameters and performance.
Overall a segmented approach is being used, e.g. fertility
and embryonic development, embryofetal development,
and prenatal and postnatal development. Assessment of
developmental and reproductive toxicity (DART) is
commonly done in rodents (mice and rats) and in rabbits
(mainly developmental toxicity). However, depending on
the metabolism, target organ and specificity of the test item,
nonhuman primate models are needed for DART evalua-
tion. This is particularly relevant for biopharmaceuticals
which frequently require the use of nonhuman primates
owing to the species-specificity of test item activity
(
Chapman et al., 2009; Martin et al., 2009
). Hence, a need
for DART studies using the nonhuman primate model is
frequently encountered with biopharmaceuticals, and
nonhuman primates have become an essential species for
DART evaluation of monoclonal antibodies (
Pentsuk and
van der Laan, 2009; Martin and Weinbauer, 2010
).
Table 19.1
provides general advantages and disadvan-
tages of various nonhuman primate species with regard to
DART safety assessment. Overall, nonhuman primates
generally offer several advantages over rodents and rabbits
with regard to DART because of similarity to humans,
e.g. endocrinology of testicular and ovarian function,
endocrinology of early pregnancy, placental morphology
and physiology, timing of implantation, rates of embryonic
