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Preclinical toxicology evaluation
Speaker Profile
 Dr
M R Marathe Advisor - Toxicology Sun Pharma Advanced Research Centre, Vadodara
Dr M R Marathe is the senior most regulatory toxicologist and pathologist in
India in new drug discovery research with over 33 years experience. He is also
associated as toxicologist and pathologist with CIBA-GEIGY, Ranbaxy, IDPL and
Lupin Ltd in New Drug Discovery Centres. He is also the principle investigator
of several preclinical studies carried out in overseas CROs.
Dr Marathe was the co-study director at Southern Research Institute, Birmingham,
USA., 1999 and also the co-ordinator for pre-IND meetings with Food and Drug
Authority (USA) and other regulatory agencies. He has successfully submitted
12 INDs and NDAs.
Qualifications and experience:
- Bachelor of Veterinary Science (BV Sc & AH)
with Honours from Bombay Veterinary College in 1965.
- Master of Veterinary Science (MV Sc) in Pathology
with distinction from Bombay Veterinary College in 1970.
- Fellow of International Biographical Association,
UK, with citation (1989).
- US FDA good laboratory practice (GLP) certification,
Princeton, NJ USA (1996).
- Beagle dogs: Training of breeding techniques at
Marshall Farms, Syracuse, USA (1996).
- Guide to PhD students in Toxicology science.
- Member of Review Committee: Indian Journal of Pharmacology.
Synopsis
Toxicology is a science to study adverse-effects of chemicals or physical agents
on biological system and preclinical toxicology is a science to evaluate safety
of a candidate drug (mostly) in animals to decide if the candidate drug is safe
for human use or not.
If we look at the history of modern preclinical toxicology, it is just about
30 years old. In early 50s the drugs were approved with just acute toxicity
study in rodents. After tragedies like thalidomide, entire world was shocked
and rules were promulgated. The present eminent position of preclinical toxicology
testing has now been established through GLP regulations.
Objectives of preclinical toxicology evaluation are to identify circumstances
under which the candidate-drugs produce toxic effects. It also establishes toxic
dose and safe dose/s, target organs of toxicity, onset, duration and reversibility.
These studies help clinician to select safe dose/s during clinical trials and
later on to determine therapeutic doses.
Pharmacokinetics and toxicokinetics studies are simultaneously carried out to
establish ‘safe’ and ‘toxic’ exposure levels and saturation
kinetics. Tissue distribution studies in animals help to locate depositions
of drug across the organs while ADME studies give details of metabolites and
their effects.
The designing of the studies, dose selection, species, number and age are critical
issues and the role of toxicologist together with pathologist become very important
to decide fate of the new drug-candidate.
Standard battery of tests of preclinical evaluation for IND and NDA submissions
are more or less defined in the guidelines with a view to guide clinician to
decide FHD in phase I/II clinical trials.
The tests include acute, subacute, genotoxicity, local, immuno toxicity and
phototoxicty for IND and chronic, reproduction toxicity , additional genotoxicity
studies and carcinogenicity studies for NDA/marketing permission. In 1979 US
FDA and later on in 1981 OECD countries formed GLP guidelines to bring uniformity
in preclinical evaluation testing methods. Stringent rules and test guidelines
were established for methodology to carry out preclinical toxicology evaluation
of new drugs. GLP guidelines have been accepted across the world including India.
To monitor the studies, quality assurance units (QAU) were formed. Recently
for paediatric drugs a separate preclinical evaluation, in juvenile animals,
has been recommended.
We know that all chemicals are harmful. However, there are harmless ways to
use these. Preclinical toxicology evaluation shows the ways.
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