Biomedical Engineering Reference
In-Depth Information
et al., 2008
). Pregnancy duration in the cynomolgus
monkeys is around 160 days (
van Esch et al., 2008
). The
first 50 days of gestation and birth pose the highest risk for
post-implantation losses and total losses across entire
pregnancy plus term can attain 50% (
Jarvis et al., 2010
).
For these reasons, physical mating is not used to assess
fertility in nonhuman primates, but clinical endpoints are
used instead. Another factor to consider is that social
housing and associated hierarchy structure among
nonhuman primates can have a profound effect on repro-
ductive parameters (
Weinbauer et al., 2008; Czoty et al.,
2009; Niehoff et al., 2010
).
For developmental toxicity studies, the number of
fetuses/infants available for evaluation is lower than the
number of pregnant monkeys entering the study. The
principles governing the number of animals to use in DART
studies are described in international guidelines. According
to the ICH S5 guideline “Detection of Toxicity to Repro-
duction for Medicinal Products & Toxicity to Male
Fertility,” a litter size of 16
marmosets and the number of live fetuses at cesarean
section ranges from one to four. Prenatal loss was close to
20%. Controlled embryofetal studies in the marmoset
suggest that marmosets might provide a relevant alternative
model for embryo/fetal toxicity evaluation if macaque
models cannot be used. The feasibility of pre- and postnatal
studies in marmosets is currently being investigated.
Unlike in rodents, multigeneration studies
at least
e
over the past years
have not been conducted for safety
assessment simply because of the extended time frames
e
e
such experiments would require 5
8 years in macaques
and approximately 4 years in marmosets. Recent guideline
changes provoked an increased demand for sexually mature
nonhuman primates since it is possible now to evaluate
reproductive toxicity in the context of a more generalized
safety assessment study, thus avoiding the need to carry out
studies focusing specifically on male and female fertility.
Related to the specifics of the breeding system, marmosets
used for safety assessment studies are always sexually
mature when leaving the breeding colony. For macaques
with highly variable and comparatively late achievement of
sexual maturity (
Table 19.1
), it has become a matter
of discussion of how to ascertain sexual maturity. Because
of the inherent extreme variability it is the authors'
recommendation to use functional endpoints rather than
numeric criteria (e.g. age, body weight, hormone levels,
etc.) for sexual maturity assessment. The authors' proposed
functional endpoints for assessing sexual maturity are the
presence of sperm in semen samples and the evidence of an
ovarian cycle based upon continued vaginal swab collec-
tion and analysis.
e
20 is recommended for rodents
and rabbits. Historically, despite known concerns about
variability of pregnancy losses, the group/litter size used in
nonhuman primate developmental toxicity studies has
generally been smaller compared to rodent/rabbit studies,
e.g. group sizes rather than litter sizes of 10
e
20. More
recently, embryofetal and pre-/postnatal study types can be
combined (
Stewart, 2009
) with group sizes of 16
e
20
(
Chellman et al., 2009
), and recently group sizes of 20 have
been recommended for this study type (
Martin and Wein-
bauer, 2010
).
Owing to the development of therapeutic antibodies
with limited cross-reactivity, a need for DART studies in
the marmoset model has occasionally been encountered. In
general, reproductive physiology and endocrinology of
marmosets are substantially different from those in Old
World monkeys and humans (
Abbott et al., 2003
) and the
clinical relevance of the marmoset for DART assessment is
unclear (
Z¨hlke and Weinbauer, 2003
). Several major
differences in reproductive physiology between marmosets
and Old World primates are well described: lack of
menstrual bleeding (ovarian cycle monitoring is based upon
progesterone-induced luteolysis and subsequent moni-
toring of progesterone levels), multiple ovulation (2
e
Bone Toxicity
Nonhuman primates are generally very useful as preclinical
models for assessing bone toxicity (
Jerome and Peterson,
2001
), the reason being that bone structure and bone
metabolism in macaques closely resembles that in humans.
Unlike in rodents, bone metabolism is characterized by
a continuous interplay of bone resorption and apposition.
Also the endocrine control of bone growth and turnover is
very similar for macaques, e.g. cynomolgus monkey, and
humans. It is critical that adult animals are being used for
bone safety assessment studies. Epiphyseal closure and
cessation of longitudinal bone growth is achieved between
the ages of 5 and 10 years (
Zoetis et al., 2006; Lees et al.,
2007
). Observations from the authors' colony suggest that
adulthood is achieved not before 6 years of age (
Partsch
et al., 1999, 2000
). Female reproductive aging compatible
with human menopause has been described for a variety of
nonhuman primate species (
Bellino and Wise, 2003
)
including the cynomolgus monkey (
Kavanagh et al., 2005
).
Importantly, nonhuman primate menopause occurs rather
late in life, e.g. postmenopausal cynomolgus monkeys were
4ova/
cycle), twin pregnancies as default, hematopoietic XX/XY
chimerism, possible germline chimerism, lack of luteiniz-
ing hormone with chorionic gonadotropin fulfilling the role
of LH in both sexes, and the absence of genes essential for
male fertility in Old World primates.
Table 19.1
summa-
rizes key advantages and disadvantages of the marmoset
model for DART studies. Ovarian cycle monitoring and
embryo/fetal development timing relative to pregnancy
duration are different for marmosets compared to
macaques. Pregnancy duration is around 145 days (
Fuchs
and Weinbauer, 2006
). Twin litter
e
is the default
in
