EXTRAPOLATION OF IN VITRO DATA TO PRECLINICAL TO HUMANS

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

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

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

 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

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.

 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

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

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

Calculations based on:
1) Animal pharmacokinetic data
2) Administered doses
3) Observed toxicities
4) Algorithmic calculation

 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

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

 STEP 1: NO OBSERVED ADVERSE EFFECT LEVEL
DETERMINATION
 The NOAEL is a generally accepted benchmark for
safety when derived from appropriate animal
studies.

 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.

 (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.

 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.

 STEP 2: HUMAN EQUIVALENT DOSE
CALCULATION

 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.

 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

 STEP 4: APPLICATION OF SAFETY FACTOR
 STEP 5: CONSIDERATION OF THE
 PHARMACOLOGICALLY ACTIVE DOSE(PAD)

 Methods of scaling drugs ( methods of extrapolation
of data )
1. Linear extrapolation/simple scaling/isometric
scaling method
2. Non linear extrapolation/allometric scaling method

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.

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

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

Figure changes as a function of size.

Interspecies difference between PK phase
 Body metabolic rate
 Species differences (size independent)
 Rate of drug distribution

 Protein binding (Size independent)
 Drug metabolism
 Drug elimination

EXTRAPOLATION OF IN VITRO DATA TO PRECLINICAL TO HUMANS

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