Thursday, 16 May 2013

Role of Preclinical Toxicology studies in Clinical Research


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.


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.
Distribution [D]:
  • 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:

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].


Raji Radhakrishnan S (Student of ACRI)

Tejeswani (Academic Coordinator)

Dr Smita Singh (Head of Academics)

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