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EXTRAPOLATION OF IN VITRO DATA TO PRECLINICAL TO HUMANS
1. KARNATAKA COLLEGE OF PHARMACY
DEPARTMENT OF PHARMACOLOY
PHARMACOLOGICALAND TOXICOLOGICAL SCREENING METHODS
PRESENTATION ON
EXTRAPOLATION OF IN VITRO DATA TO PRECLINICAL TO HUMANS
PREPARED BY : SUDARSHAN SINGH
2. Extrapolation of in vitro data to preclinical to humans
Content
Introduction of in vitro and/ in vivo studies
Introduction of preclinical studies
Extrapolation of in vitro data to preclinical
Extrapolation of preclinical dat a to humans
3. Extrapolation of in vitro data to preclinical to humans
in vivo studies
Are the latine word (means with in the living )
Are those in which the effects of various biological
entities are tested on whole,
living organisms or cells, usually animals, including
humans, and plants
4. Extrapolation of in vitro data to preclinical to humans
animal testing and clinical trials are major elements
of in vivo research
In vivo testing is often employed over in
vitro because it is better suited for observing the
overall effects of an experiment on a living
subject. In drug discovery,
example, verification of efficacy in vivo is crucial,
because in vitro assays can sometimes yield
misleading results with drug
5. Extrapolation of in vitro data to preclinical to humans
Professor
Harry Smith found that sterile filtrates of serum from
animals infected with Bacillus anthraciswere lethal for
other animals,
whereas extracts of culture fluid from the same organism
grown in vitro were not
In microbiology Once cells are disrupted and individual
parts are tested or analyzed, this is known as in vitro.
6. Extrapolation of in vitro data to preclinical to humans
in vitro studies
("within the glass"),
i.e., in a laboratory environment using test
tubes, petri dishes, etc.
Examples of investigations in vivo include: the
pathogenesis of disease
16. Extrapolation of in vitro data to preclinical to humans
Extrapolation of in vitro data to preclinical
to humans
Estimating the first in human (FIH) dose is one of
the initial steps in the clinical development of any
molecule that has successfully gone through all of the
hurdles in preclinical evaluations
19. Extrapolation of in vitro data to preclinical to humans
ESTIMATING THE MRSD-METHODS
1) NOAEL Method
2) MABEL Method
3) Similar Drug Comparison Method
4) Pharmacokinetic Guided Approach
5) PK/PD Modelling Guided Approach
20. Extrapolation of in vitro data to preclinical to humans
Calculations based on:
1) Animal pharmacokinetic data
2) Administered doses
3) Observed toxicities
4) Algorithmic calculation
21. Extrapolation of in vitro data to preclinical to humans
NOAEL METHOD
The NOAEL method is based on selecting a dose
with minimal risk of toxicity, rather than selecting
one with minimal pharmacologic activity in humans
22. Extrapolation of in vitro data to preclinical to humans
Steps using animal toxicology data:
1) Determine No Observed Adverse Effect Level (NOAEL) ‰
2) Convert NOAEL to Human Equivalent Dose (HED) ‰
3) Select most appropriate species ‰
4) Apply Safety Factor ‰
5) Consider Pharmacologically Active Dose
23. Extrapolation of in vitro data to preclinical to humans
STEP 1: NO OBSERVED ADVERSE EFFECT LEVEL
DETERMINATION
The NOAEL is a generally accepted benchmark for
safety when derived from appropriate animal
studies.
24. Extrapolation of in vitro data to preclinical to humans
STEP 2: HUMAN EQUIVALENT DOSE CALCULATION
After the NOAELs in the relevant animal studies
have been determined, they are converted to human
equivalent doses (HEDs) using appropriate scaling
factors.
The most appropriate method for extrapolating the
animal dose to the equivalent human dose should be
decided.
25. Extrapolation of in vitro data to preclinical to humans
(doses scaled 1:1) between species when doses are
normalized to body surface area (mg/m2).
These are recommended as the standard values to
be used for interspecies dose conversions for
NOAELs.
26. Extrapolation of in vitro data to preclinical to humans
HED = Animal NOAEL x (W animal/W human)(1-b)
Conversion factors = (W animal/W human)(1-b)
Conventionally, for a mg/m2 normalization b would be 0.67,
but studies have shown that MTDs scale best across species
when b=0.75.
Conversion factors are calculated over a range of animal and
human weights using (Wanimal/Whuman)0.33or
(Wanimal/Whuman)0.25 to assess the effect on starting dose
selection of using b = 0.75 instead of b = 0.67.
27. Extrapolation of in vitro data to preclinical to humans
STEP 2: HUMAN EQUIVALENT DOSE
CALCULATION
29. Extrapolation of in vitro data to preclinical to humans
BASIS FOR USING Mg/Kg CONVERSIONS
The “mg/kg” scaling will give a 12-,6- & 2- fold
higher HED than the default mg/m2 approach for
mice, rats, and dogs, respectively.
32. Extrapolation of in vitro data to preclinical to humans
STEP 3: MOST APPROPRIATE SPECIES
SELECTION
Factors that could influence the choice of the most
appropriate species:
(1) Differences in the absorption, distribution,
metabolism, and excretion (ADME) of the
therapeutic between the species
33. Extrapolation of in vitro data to preclinical to humans
STEP 4: APPLICATION OF SAFETY FACTOR
STEP 5: CONSIDERATION OF THE
PHARMACOLOGICALLY ACTIVE DOSE(PAD)
37. Extrapolation of in vitro data to preclinical to humans
Methods of scaling drugs ( methods of extrapolation
of data )
1. Linear extrapolation/simple scaling/isometric
scaling method
2. Non linear extrapolation/allometric scaling method
38. Linear extrapolation (method no.1)
mg/kg dose established for one species is applied across
all species
Advantage :
simple
Problems arise when this method is applied to other
species
This method assumes that
any differences in species PK/PD are not clinically
relevant
Dosage and weight are directly (linearly) proportional.
39. Drawbacks of method no.1
This method tends to overdose large animals and
underdose small animals, which may be very
clinically significant.
Typically, this method is only effective with drugs
that have large margins of safety and wide
therapeutic ranges
40. Allometric scaling (method no.2)
drug pharmacokinetics has a nonlinear (allometric)
relationship to weight.
Allometric scaling has become the method of choice for
interspecies extrapolation in drug discovery and
development.
It is the study of size and its consequences
Based on the principle that major physiologic processes
are related to body weight raised to allometric exponent