Biomedical Engineering Reference
In-Depth Information
22
31 years old (
Kavanagh et al., 2005
). For practical
reasons, bone metabolism and toxicity studies are con-
ducted in nonhuman primates using experimentally
induced menopause using ovariectomy (
Jerome and
Peterson, 2001; Vahle et al., 2008
) followed by immediate
test item replacement to prevent bone loss or initiation of
treatment after a period of 6 months or longer in order to
study stimulation of bone mass and density.
A variety of parameters are available to analyze bone
metabolism and function: Serum and urine bone turnover
markers such as bone specific alkaline phosphatase, cross-
linked C- and N-terminal telopeptides of type I collagen
(CTX and NTX), osteocalcin, and others. For lumbar and
femoral bone mineral density and bone mineral content,
dual energy X-ray absorptiometry (DXA) analysis is
established. In addition, peripheral quantitative computed
tomography (pQCT) enables analysis of cortical and
trabecular bone mineral density using a variety of bones
including vertebrae, femur, hip, tibia, and radius. Finally,
bone histomorphometry and bone biomechanical analysis
(bone strength) are also established. Bone architecture can
be described in detail using histomorphometry as well as
noninvasively using high resolution CT (micro-CT) scan-
ning. Bone strength, perhaps the most important factor
defining bone quality, can be determined through tests
performed on long bone or spine. It is established that
ovariectomies provokes bone loss by increased bone turn-
over and induced trabecular bone loss (
Iwamoto et al.,
2009
). Bone physiology has also been studied in male
macaques, but female macaques following ovariectomy are
being used frequently (
Bagi et al., 2008; Olson et al., 2008
).
Whereas bone physiology is comparable between
macaques and humans, the timing of postnatal bone matu-
ration is quite different. For example, skeletal maturation,
assessed by bone radiographic analysis, is comparatively
accelerated in the cynomolgus monkey with bone age in
6-month-old animals corresponding to that of a 7-year-old
human (
Partsch et al., 1999, 2000
). For the newborn rhesus
monkey, ossification of limbs resembles that of a 5- to
6-year-old human (
Zoetis et al., 2006
). Based upon radio-
graph analysis of the left hand and wrist based upon the
human Tanner TW2-RUS staging (
Tanner et al., 1983
), it
would appear that cynomolgus monkeys should be at least 7
years old when bone maturation is considered completed.
in the development of biological therapeutics there is more
need to perform these types of studies in the nonhuman
primate, as they are often the only species with relevant
receptor populations. In addition, as the cost of clinical
development of new pharmaceuticals has risen, many
pharmaceutical companies are looking for more definitive
efficacy data than the rodents species alone can provide
before they commit to clinical development of a molecule.
Efficacy studies in the nonhuman primate, as opposed to
rodent studies, pose some unique challenges that should be
considered before embarking on a Discovery program.
Many scientists working in Discovery research have
very little experience with the nonhuman primate as a test
species. Rodent efficacy models, whether run in normal or
diseased rodents, are generally performed with fairly
homogeneous animals that can be placed in a study in large
enough numbers to allow for statistical evaluation of
results. In contrast, nonhuman primates tend to be more
heterogeneous individuals with more genetic, behavioral,
age (sexual maturity), and health history variation than is
seen in rodents. Generally, smaller numbers of animals are
placed on these nonhuman primate studies because of the
cost and logistics of acquiring and handling the animals,
and also because test article availability is often limited in
this phase of drug development. This all creates studies that
are more like Phase 1 clinical trials, where you have small
numbers of individual patients. Often only descriptive
statistics are used, and each animal is used as its own
control. This can make it very difficult to demonstrate
subtle efficacy endpoints. Individual patient issues need to
be addressed and assessed for their impact on study
outcomes. For example, results of a study designed to
evaluate electrolyte homeostasis will be impacted by an
individual animal that develops diarrhea, a common clin-
ical sign in the nonhuman primate (
Blackwood et al.,
2008
). Handling stress can also cause significant variability
in a number of parameters (hormone levels, cardiovascular
endpoints), so studies must be designed such that dosing
and sample collection events do not invalidate measured
endpoints (
Evron et al., 2005
).
Biomarker development is also an important consider-
ation when developing an efficacy program (
Ingram et al.,
2001
). Assay development and validation for the nonhuman
primate species will often need to be done, and minimizing
blood sample volume requirements through assay
management will greatly impact the amount of data that
can be collected from these studies.
e
EFFICACY STUDIES IN THE NONHUMAN
PRIMATE
Comparison to Use of More Common
Species
Historically, most efficacy (Discovery) modeling has been
performed in the rodent species; however, with the increase
Use of Normal Animals or Models of
Disease
Scientists will also need to decide if their efficacy model
requires diseased animals or whether the efficacy endpoints
