Biomedical Engineering Reference
In-Depth Information
studies; and the potential for theoretical toxicity(s) to occur
in clinical trials.
control. Nonclinical safety studies with PPAR- g in cyn-
omolgus monkeys show a consistent set of drug-induced
effects. PPAR- g causes fluid accumulation, weight gain,
edema, proliferation of white and brown fat, and an
increased incidence of chronic heart failure ( Aleo et al.,
2003 ). Bladder urothelial changes occur in monkey, as with
rat, which cause concern for neoplasia ( Hardisty et al.,
2008 ). Nonhuman primates have not predicted adverse
events of hepatic and cardiovascular toxicity that have
occurred with marketed drugs in humans. Given these are
low incidence events in humans ( Gale, 2001 ), it is not
unexpected that nonhuman primate and other animal species
did not detect these toxicities.
PPAR- a is used to produce a more desirable lipid profile
in humans by increasing HDL and decreasing triglyceride
levels. Dyslipidemia occurs in the metabolic syndrome
phase that precedes development to T2DM. PPAR- a , was
the first form of PPAR to be identified. It is produced
primarily in the skeletal muscle and the liver, where it is
involved in the body's breakdown and transport of fatty
acids. PPAR- a drugs given to healthy cynomolgus
monkeys cause peroxisome and mitochondrial prolifera-
tion, hepatocellular hypertrophy from smooth endoplasmic
reticulum reduplication, and increased liver weight. These
changes occur without hepatocellular proliferation, and
thus do not likely have the hepatocarcinogenic liability that
occurs with rodent ( Hoivik et al., 2004 ).
Dogs have been used to study the toxicity of DPP-IV
inhibitors, which causes severe toxicity. DPP-IV causes
a skin lesion in nonhuman primates, prompting the FDA to
require testing all DPP-IV inhibitors in monkeys. Data from
these studies should clarify whether skin lesions are due to
DPP-IV inhibition itself or to some other mechanism of
action ( Chyan and Chuang, 2007 ).
Exenatide, a large molecule, synthetic version of
exendin-4, a hormone found in Gila monster saliva, is
marketed for treatment of T2DM. It is an insulin secreta-
gogue and GLP-1 receptor agonist with glucoregulatory
effects to be used with other oral therapies, such as met-
formin or metformin and a sulfonylurea, for glycemic
control in T2DM. Nonclinical multidose studies were done
in cynomolgus monkeys, rats and mice, with no adverse
drug-induced effects occurring in studies of up to 9 months'
duration. After 3 months' dosing, subtle hyperplasia of
pancreatic islets occurred in monkeys. Anti-drug antibodies
formed in monkey, but did not alter clearance or the
pharmacological effect (NDA 21 e 919: Exenatide).
Diabetes
Old World primates are good models for human type 2
diabetes mellitus (T2DM). Like humans, the disease is
naturally occurring, has similar onset and progression, and
occurs at an increased incidence with increased age and
obesity ( Cefalu, 2006; Wagner et al., 2006 ). T2DM can also
be induced with streptozotocin in Old World primates;
however, marmosets are a poor model as they require
greater doses of streptozotocin and develop complicating
renal and hepatic toxicity. Type 2 diabetes mellitus onset is
characterized by obesity-associated peripheral insulin
resistance accompanied by a compensatory increase in
insulin levels. During this pre-T2DM phase, which is
described as “metabolic syndrome,” fasting plasma glucose
levels remain normal and there is an onset of dyslipidemia
and hypertension. This is followed by decreased insulin
secretion and corresponding increased fasting glucose
levels leading to T2DM. It may take years for the disease to
fully progress. Histopathological changes are also similar
to those in humans with T2DM. As with human disease,
these consist of islet cell hyperplasia, increased islet
amyloid with loss of beta cells, and vascular (both micro
and macro) and cardiovascular disease.
Nonhuman primates with T2DM are used for disease
mechanism research and studying the efficacy of potential
drug candidates. Standard anti-diabetic treatments have
included insulin, a hormone which directly controls plasma
glucose levels, biguanides and sulfonylureas which stimu-
late insulin secretion, and thiazolidinediones (peroxisome
proliferator-activated receptor- g [PPAR- g ]) which regulate
genes controlling the expression and translocation of
glucose receptors. New categories of antidiabetes drugs are
being developed including dipeptidyl peptidase inhibitor
(DPP-IV
an oral hypoglycemic drug), glucagon-like
peptide (GLP-1
e
a parenterally administered peptide
receptor agonist), and a sodium-glucose cotransporter
inhibitor (SGLT-inhibitor
e
an oral inhibitor of gut and
renal glucose uptake). Nonclinical efficacy studies are done
in disease models of multiple species.
Toxicity studies for the development of anti-diabetic
drugs have been done in healthy cynomolgus and rhesus
monkeys. A class of structurally diverse small molecule
drugs being developed for T2DM is peroxisome proliferator-
activated receptors (PPAR) ( Aleo et al., 2003; Schafer et al.,
2004 ). There are three different forms of PPARs: PPAR- a ,
PPAR- g , and PPAR- d (also called PPAR- b ). PPAR- g is
made primarily in fat cells and affects the production of fat
cells and the metabolism of lipids and reduces insulin
resistance. Insulin-resistant and diabetic monkeys have been
found responsive to PPAR- g agonists, resulting in glycemic
e
Antivirals
Nonhuman primates provide good models for human viral
diseases. These models have played an important role in
demonstrating preclinical efficacy of novel antiviral drugs,
determining treatment
regimens for HIV infection in
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