Biomedical Engineering Reference
In-Depth Information
humans, the intended target population for the drug, as well
as providing a nonlethal testing alternative.
ADME studies are generally non-GLP studies, and while
they are not establishing drug safety per se nor are they
specifically intended for submission to a regulator such as
the Food and Drug Administration, they are critical to
building a body of literature around a novel compound.
Important information gathered during ADME investiga-
tions can allow researchers to “fail” unpromising
compounds early in the process, leaving more resources
available for investigating compounds with greater medical
potential. ADME investigations can also be useful in iden-
tifying potential safety concerns related to active metabo-
lites of a compound. Further, drug developers employ
a decision tree approach in determining which metabolites
may require specific safety investigations (
Baille et al.,
2002; Smith and Obach, 2006; Guidance for Industry:
Safety Testing of Drug Metabolites, 2008
) using a combi-
nation of data from in vitro, animal, and human studies.
repeat dose toxicology studies on nonrodent animal
models. While canines and nonhuman primates are both
commonly used nonrodent models for cardiovascular
assessment (required under FDA testing protocols), the
nonhuman primate is chosen preferentially when molecule
binding or metabolites produced are specific for human and
nonhuman primates. In addition to being the model of
choice for general safety assessment of many biological or
large molecule compounds (
EFPIA Briefing Paper, 2008;
Chapman et al., 2010
), the nonhuman primate may provide
more straightforward and applicable data related to heart
rate and rhythm than the canine even in small molecule
investigations due in part to the normal canine sinus
arrhythmia and horizontal body orientation. Any perceived
requirement for stand alone cardiovascular studies of bio-
logical products in nonhuman primates must be interpreted
cautiously, though, as the large molecule size (preventing
access and blockage of ion channels) and extreme speci-
ficity of many agents may not require cardiovascular testing
beyond inclusion of ECG and blood pressure endpoints in
standard toxicology protocols (
Vargas et al., 2008
).
The ICH guidelines also call for conscious (unanes-
thetized) data collections as the preferred method for
cardiovascular data, leading to increasing use of radio-
telemetry data collection in nonhuman primates (
Interna-
tional Council on Harmonisation, 2000
). Data collection by
telemetry has rapidly evolved into a well-developed and
reliable research methodology. Externally applied elec-
trodes covered by well-fitted protective jackets carrying
battery-powered transmitters can produce high quality
ECG data and are well tolerated by nonhuman primates.
Animals are also frequently surgically instrumented with
electrodes and transmitters that can produce ECG data
without the need for external jackets (
Henriques et al.,
2010
). Surgically implanted arterial pressure probes
provide direct measure of arterial blood pressure that can be
collected remotely, unaltered by external factors (
McMa-
hon et al., 2010
), but noninvasive methods are available that
yield high quality data in restrained animals. High defini-
tion oscillometry has been shown to produce reliable data
in conscious restrained animals with good correlation to
telemetry blood pressure data (
Schmelting et al., 2009;
Mitchell et al., 2010
). In all, telemetry data collection
systems avoid the artifacts associated with chemical or
physical restraint and influences of sympathetic nervous
system arousal produced by people in the room. They allow
for extended periods of calm, noise-free data which is
optimum for the detection of drug-induced affects on the
cardiovascular system.
Cardiovascular Models
Cardiovascular safety assessment is a core component of
testing programs that evaluate new pharmaceuticals inten-
ded for the human medical market. The guidance document
Safety Pharmacology Studies for Human Pharmaceuticals,
ICH S7A (
International Council on Harmonisation, 2000
),
defines a core battery of studies of vital organ system
function, i.e. those systems considered so crucial to life that
even a momentary disruption could be fatal. The core
battery consists of tests of the drug effects on the cardio-
vascular system, the central nervous system, and the
respiratory system. A second guidance document,
ICH S7B
(2005)
, is strictly focused on assessing the potential for QT
interval prolongation, a potentially deadly event. Prolonged
QT (delayed ventricular repolarization) increases the risk
of ventricular tachycardia including torsade de pointe
(TdP) (
Yap and Camm, 2003
). Many membrane ion
channels (sodium, calcium, and potassium) and transporter
functions are involved in the complex process of ventricular
repolarization, several of which are known to be inhibited
by pharmaceuticals (
International Council on Harmo-
nisation, 2005
). Of particular importance is the rapid
potassium channel (IKr). While IKr blockers may also
affect other sodium or calcium channels, that additional
activity appears to negate the IKr blocking effect. When
a hERG assay detects IKr channel blocking activity, it may
serve as a signal for in vivo investigation of the functional
impact of that activity.
In vivo cardiovascular testing protocols include
assessment of blood pressure, heart rate, and electrocar-
diogram and additional studies as needed, including cardiac
function studies. Initial data of electrocardiograms (ECG)
and blood pressure measures are collected in the course of
Central Nervous System Models
Assessing the safety of new drugs and compounds in
relation to their effects on the CNS is critical to drug
