Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 1 PRINCIPLES OF CLINICAL PHARMACOLOGY
undertaking a clinical study to evaluate the efficacy of
a treatment in order that one can clearly separate
pharmacodynamic and placebo effects. Recognizing the
existence and possible benefits of placebo effects, it is
good practice to maximize use of the placebo effect to
supplement the pharmacological response to treatment,
although the effect may not be sustained and may be a
source of variability in response with time.
DEVELOPMENT OF NEW ANIMAL DRUGS
In approving new animal drugs, regulatory agencies
must first be satisfied with the efficacy, safety and quality
of the proposed new product. While each regulatory
agency has a unique set of requirements that must be
satisfied, common to all is the high quality and integrity
of information that is currently demanded and supplied.
The development of a new animal drug product is a
costly, time-consuming and high-risk exercise. It is estimated
that from discovery to marketing of a new chemical
entity for a companion animal can take 6–8 years,
cost in the order of US$100m and result from the selection
of one candidate from thousands originally screened
for biological activity.
Clearly, the development of new animal drugs can
only be undertaken by large companies with the appropriate
competencies, skills and commitment. To lessen
the risks associated with investment in drug candidates
that will not ultimately meet the stringent requirements
of the regulatory agencies or the marketplace, it is critical
that developers can clearly identify as early as
possible in the development process the limitations of
candidate molecules. Successful new animal drugs must
satisfy a clinical need and be effective, safe and economically
acceptable. Decisions concerning the therapeutic
areas to which to devote development resources will
consequently require a blend of scientific and commercial
considerations. Because of the high costs and the
inherent need to achieve a financial return on the investment,
many minor therapeutic needs will be left without
approved animal drugs for treatment and require the
use of alternative remedies, e.g. human drugs.
Much of the high cost of bringing a new animal drug
to market is associated with the manufacturing and
preclinical (especially toxicity testing) requirements. In
many cases this cost can be reduced by selecting for
development those compounds already under development
or approved for human or agricultural use.
Examples of development cost reduction include the
development of enrofloxacin (the N-ethyl analog of ciprofloxacin)
for animals, having previously developed
ciprofloxacin for humans; the application of enalapril
in dogs, having established its use in humans; the development
of imidacloprid and fipronil for dogs and cats,
having initially developed these actives for agricultural
pest control.
Complete details of the requirements of individual
agencies for the approval of new animal drugs can be
obtained by consulting the appropriate web addresses
provided earlier. A summary of the process from discovery
to marketing and beyond is presented below.
Discovery
While new indications for an existing drug may arise
from astute observations during treatment of patients
for approved indications (e.g. unexpected control of
erythema nodosum leprosum noted when thalidomide is
used as a soporific in lepers; botulinum toxin type A
originally approved for treatment of strabismus and
blepharospasm associated with dystonia and found
useful for temporary improvement in the appearance
of moderate-to-severe glabellar lines associated with corrugator
and procerus muscle activity; sildenafil for diabetic
gastroparesis arose from astute observations during
treatment of patients for erectile dysfunction), the most
fruitful area of discovery is the biological screening of
new chemical entities (NCEs). NCEs may be derived by
chemical synthesis (e.g. fluoroquinolones), by screening
of secondary metabolites elicited by fermentation of
micro-organisms (cyclosporin, penicillin and ivermectin)
or from extracts of plants or animals (digitalis glycosides
from foxglove, morphine from poppies, salicylic acid
from willow bark, insulin from pancreas).
Recently there has been renewed interest in evaluating
the traditional remedies of various indigenous peoples.
Compounds such as digoxin, quinine, aspirin and morphine
were discovered historically in this way and more
recently a number of antimalarial and antineoplastic
compounds have been identified in ethnobotanical
investigations. Other natural sources of NCEs include
the toxins of snakes, spiders and marine organisms,
bacterial and fungal metabolic products (including antibiotics,
anticoccidials and other pesticides) as well as
antibiotic products from insects and amphibians.
Chemical synthesis is often directed by planned threedimensional
structure–activity analysis of known interactions
with isolated receptors. The most recent source
of NCEs has emerged from the genomic, proteomic,
transcriptomic and metabolomic revolutions. By isolating
and identifying genes and proteins involved in
disease processes (either in the mammalian host or a
pathogen) it is possible (in theory) to identify receptors
and pharmacophores and use them to guide development
of novel agonists or antagonists that may serve
important therapeutic roles.
In vitro broad-spectrum high-throughput screens
have been developed to quickly characterize the biological
activity of NCEs, identifying propensity for tissue
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