Abstract:
Preclinical
studies are carried out on animal models prior to the onset of clinical trials
in humans. Various parameters need to be considered in preclinical studies
before the drug is actually tested on humans. Important factors include
pharmacokinetics data, pharmacodynamics data, drug safety and toxicology data.
The goals of preclinical studies include: predicting the safety, efficacy,
toxic effects, dose dependence and further to extrapolate it for potential
human outcome.
Introduction:
Preclinical
phase is the stage of drug development process that begins before clinical
trial actually starts during which the feasibility, iterative testing and drug
safety data are collected. Other non clinical studies include pharmacology
studies for safety assessment [safety pharmacology] and pharmacokinetic [ADME]
studies. The above mentioned studies provide a myriad of information about the
drug and how they might act during clinical trials. Drugs will undergo PK, PD
and toxicity studies through animal testing.
Importance of Pharmacokinetics
and Pharmacodynamics data:
Absorption [A]:
- Helps to decide on routes of administration.
- Helps to decide on dosage level.
- Helps to know the impact the drug has created
- Helps to study the Bioavailability of the drug [rate of bound and unbound drug]
Metabolism [M]:
Conjugation Data ,Cumulative effect, Therapeutic effect, Toxic effect.
Excretion [E]:
Helps to know the excretion rate
of the drug from the body.
Some
other parameters which could be derived from PK/PD studies are efficacy,
potency, drug concentration levels in plasma, cmax, tmax, bioavailability and t1/2
life. Secondary parameters include data on AUC [Area under the Curve] which is
a measurement of how much drug is absorbed by the body and how easily it is
eliminated. Pharmacodynamics studies also gives data about permeability of
barrier, pH and binding capacity.
Preclinical toxicology studies:
Goal:
Invitro tests are used to evaluate the long term safety of a drug. It helps to determine specific properties of a drug and also helps to assess mutagenic and carcinogenic effects leading to toxicity. Toxicological activity of the products can be determined using invitro and invivo assay methods which estimate the clinical relatedness of the toxicological effects of the drug.
(i) Invitro methods:
Objective:
To study the
action of the test drug in tissues and cells from different organisms. This
helps to study the mutagenic and carcinogenic property of a drug.
Tissues
from several species including man can be examined and it also helps to reduce
the number of animal tests required for screening new drugs. These studies help
us to know certain factors like genotoxicity and mutagenicity. Genotoxicity
refers to the study of toxic effects of the drugs on genetic/molecular level.
The methods used in genotoxicity studies are molecular profiling and whole
genome analysis.
High
throughput profiling of a gene or a protein could reveal if there are any
potential changes in the chromosome and DNA activity in using a drug. For e.g.:
In humans, SNP [single Nucleotide Polymorphisms] are observed in which a single
gene / base pair differ from another human. Studies are carried out to see the
effect of drug on SNP’s, Haplotype genes etc using marker analysis.
Other
studies are conducted specifically on microorganisms. To determine
antibacterial property of a drug, few assays used include: Bacterial Reverse
Mutation tests [AMES test], E.coli Reverse Mutation Assay, Invitro
mammalian chromosome aberration test, Invitro mammalian cell gene
mutation test.
Assay
studies are conducted on microorganisms like Salmonella typhymurium, Escherichia
coli and yeast. Mammalian cells used are mouse myeloma cells, Chinese
hamster ovary [CHO] cells and also fully sequenced organism like Drosophia
melanogaster [fruit fly].
(ii) Invivo methods:
Objective:
The main
objective of carrying our invivo studies are to determine
the qualitative and quantitative analysis of how the drug acts on a body
and the prime determining factor being the drug safety. The studies that are
carried out inside an animal model is referred to as invivo studies. The
choices of animal model play a major role in these types of studies.
Choice
of model organisms: Differences
in gut enzyme activity and circulatory system makes certain models more
appropriate based on dosage forms. For e.g., canines are good models for solid
oral dosage forms because carnivore intestine is underdeveloped compared to
omnivores and gastric emptying rates are high. Also rodents cannot act as
models for antibiotic drugs because alteration of intestinal flora causes
significant adverse effects.
Depending
on the drugs functional group it may be metabolized in similar or different
ways between species which will affect both efficacy and toxicology. Some
commonly used traits are: those animals which breed faster, easily
availability, low cost in growing and housing, and selecting animals for which
biological profile information is already available and are already proven to
be model animals.
Ethical issues:
Invivo studies are carried out abiding
to certain guidelines put forth by PETA [People for the Ethical
Treatment of Animals] which states that animals should to be treated
respectfully.
The invivo studies can be
carried out to determine the following factors:
Objective: To determine the
safest dose to be administered. The study gives the results for MTD [Maximum
tolerated dose] and NOAEL [Non Observed Adverse Effect Limit].
References:
http://www.sciencedirect.com/science/book/9780123878151
www.pacificbiolabs.com/tox_regulatory.asp
Raji Radhakrishnan S (Student of ACRI)
Tejeswani (Academic Coordinator)
Dr Smita Singh (Head of Academics)
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