2. ICH stands for International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use.
Regulatory authorities of Europe, Japan & the United States to discuss scientific & technical aspects of
pharmaceutical product registration.
Created in April 1990 at a meeting in Brussels in Europe.
Objective to increase international harmonisation of technical requirements to ensure safe, effective and high
quality medicines developed & registered in most efficient & cost effective manner
Quality, safety, efficacy & multidisciplinary aspects of pharmaceutical substances.
Guideline No. S3A deals with conducting toxicity studies for pharmaceutical substances.
Adopted on 27th October 1994
3. GENERAL PRINCIPLES
Quantification of exposure
Amount of exposure assists in toxicity measurements in species & sexes
Exposure represented by plasma concentration or AUC
Design of toxicity studies depends on exposure & dose-dependence at therapeutic levels in humans.
Justification of time points for sampling
Time points to collect body fluids frequent, but not so much to interfere with normal conduct of study
Contribution to the setting of dose levels
a) Low dose levels
No toxic-effect dose level, exposure should equal or just exceed maximum expected in humans
b) Intermediate dose levels
Multiples of exposure at lower dose levels
c) High Dose levels
Lowest dose level producing maximum exposure accepted as top dose level
4. Extent of exposure assessment in toxicity studies
Concomitant toxicokinetics performed in satellite groups
Satellite groups study, small animal
Main study, large animal
no of animals used minimum for generating toxicokinetic data
both males & females if sex related differences in toxicity
Complicating factors in exposure interpretation
Species differences in protein binding, tissue uptake, receptor properties & metabolic profile
Even at low plasma conc., high levels of administered compound occur in specific organs/tissues.
Route of administration
ROS by alternative route like inhalation, topical or parenteral depends on PK properties of subs
Changing the route reduces the safety margin,
Found by comparing AUC & Cmax by existing & proposed routes
5. Determination of metabolites
When administered compound acts as 'pro-drug' and delivered metabolite is primary active entity.
When compound is metabolised to one or more active metabolites making significant contribution to
tissue/organ responses.
When administered compound extensively metabolised and measurement of plasma or tissue concentrations
of major metabolite is only practical means of estimating exposure
Statistical evaluation of data
Large intra & inter-individual variation of kinetic parameters, precision is required.
Analytical methods
Method specific for entity,
Choice of analyte & matrix to be assayed should be stated, avoid interference by sample subs
Plasma, serum or whole blood are studies
6. Reporting
Details of toxicokinetic data with evaluation of results
TOXiCOKINETICS IN VARIOUS AREAS OF TOXICITY TESTING โ SPECIFIC ASPECTS
Single โ dose toxicity studies
Performed in early phase of dev before developing bioanalytical method.
Plasma samples taken in such studies and stored for later analysis.
Results help in choice of formulation & prediction of rate & duration of exposure.
Repeated-dose toxicity studies
To find out PD/PK properties
Genotoxicity studies
Systemic exposure or characterized exposure in indicator tissue
7. Carcinogenicity studies
Sighting or dose-ranging studies
Appropriate monitoring or profiling of these studies assists in main studies
Attention to species or strains not included or routes of administration used for first time.
Main studies
Treatment regimen, species & strain selection determined based on PK/TK info
Rat & mouse
Reproductive toxicity studies
Satellite group used to collect info
a) Fertility studies
Determine dosing regimen & info available from earlier studies
b) Studies in pregnant & lactating animals
Assessment of dams, embryos, fetuses or newborn at specified days.
Milk secretion is also assessed.
