Dose translation from animals to humans requires consideration of factors beyond simple body weight scaling. Body surface area, pharmacokinetics, and species differences must be accounted for to safely determine starting doses in clinical trials. The NOAEL method is commonly used, identifying the no observed adverse effect level from animal studies and applying safety factors to determine a maximum recommended starting dose for humans. Proper selection of animal species and consideration of pharmacologically active doses can also inform translation of doses from animals to humans.

1. Dose translation from animal to human
Presented by:
Khatereh zarkesh
Ph.D student of pharmaceutics at SUMS

2. Introducation
Choosing first in human (FIH) of such drugs for research, experiments,or
clinical trials in animals and humans is a concern.
In 2005, the US Food and Drug Administration (FDA) issued guidance on
estimating the maximum safe starting dose in initial clinical trials for
therapeutics in adult healthy volunteers, which provided a framework to
carry out the estimation.
It should be emphasized that the common perception of scaling of dose
based on the body weight (mg/kg) alone is not the right approach.

3. This is primarily because the biochemical, functional systems in species
vary which in turn alter pharmacokinetics. Therefore, extrapolation of
dose from animals to humans needs consideration of body surface area,
pharmacokinetics, and physiological time to increase clinical trial safety.

4. DEFINITIONS
1) MRSD: MAXIMUM RECOMMENDED STARTING DOSE
2) LEVEL: Refers to the dose or dosage, generally expressed as mg/kg or
mg/kg/day.
3) NOAEL: NO OBSERVED ADVERSE EFFECT LEVEL (NOAEL) : The highest dose
level that does not produce a significant increase in adverse effects.
4) NOEL: NO OBSERVED EFFECT LEVEL: Refers to any effect
5) LOWEST OBSERVED ADVERSE EFFECT LEVEL (LOAEL): The lowest dose that
produces adverse effects.

5. 6) HED: HUMAN EQUIVALENT DOSE: The quantity of a chemical that,
when administered to humans, produces an effect equal to that produced
in test animals by a smaller dose.
7) MABEL: MINIMAL ANTICIPATED BIOLOGICAL EFFECT LEVELS : The
lowest dose that is associated with any biological effect, whether it be
toxicity or a desired pharmacological effect.

7. 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

8. MRSD(maximum recommended starting dose )
The NOAEL method is based on selecting a dose with minimal risk of
toxicity, rather than selecting one with minimal pharmacologic activity in
humans. This approach works well with new molecules that act on
established targets and/or have the pharmacology that is more or less
understood.
1) No observed adverse effect levels (NOAEL): the highest dose level
that does not cause significant adverse effects, is a typical index for
safety obtained from proper animal experiments to determine a safe
starting dose.

9. 2) Human equivalent dose (HED) : body surface area correction factor
which depends on the animal weight
3) select appropriate animal species: with the lowest HED is considered
most sensitive species for determining human risk and is usually selected.
4) Apply safety factor : in practice ,the MRSD for the clinical trial is
determined by divinding the HED derived from the animal NOAEL by the
defult safety factor of “10”.
5) pharmacologically active dose

10. MRSD

11. TYPES OF FINDINGS IN NONCLINICAL TOXICOLOGY
STUDIES
• Overt toxicity
• Surrogate markers
• Exaggerated pharmacodynamic effects
should be based on an effect that would be unacceptable if produced by
the initial dose of a therapeutic in a phase 1 clinical trial conducted in
adult healthy volunteers.
 PK INFLUENCE ON NOAEL

12. Allometric
• Allometric scaling is an empirical approach where the exchange of drug
dose is based on normalization of dose to body surface area.
• This method use frequently used in research for experimental purpose
to predict an approximate dose on the basis of data existing in other
species. Drugs with lesser hepatic metabolism, low volume of
distribution, and excreted by renal route are ideal candidates for scaling
of dose by this approach.

13. Conversion Based on Body Surface Area
• Doses lethal to 10% of rodents (LD10) and MTDs in non-rodents both
correlated with the human MTD when the doses were normalized to the
same administration schedule and expressed as mg/m2.
• Hence, it was concluded that the approach of converting NOAEL doses to an
HED based on body surface area correction factors (i.e., W0.67) should be
maintained for selecting starting doses for initial studies in adult healthy
volunteers.
• Since surface area varies with W0.67, the conversion factors are therefore
dependent on the weight of the animals in the studies.

14. • 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.
However, converting doses based on an exponent of 0.75 would lead to
higher, more aggressive and potentially more dangerous starting doses.

15. mg/m2 = km × mg/kg
Km = average body weight (kg) /BSA
HED (mg/kg) = Animal does (mg / kg)×( Animal Km /Human Km)
? Rat dose is 50 (mg/kg) ,HED in human body weight is 60 kg? 8.1 mg/kg

17. However, conversion between species based on mg/m2 is not supported
for drugs administered by topical, nasal, subcutaneous, or intramuscular
routes as well as proteins administered parenterally with molecular
weight >100,000 Daltons.

18. MOST APPROPRIATE SPECIES SELECTION
• Most sensitive species (i.e., the species in which the lowest HED can be
identified).
• Factors such as whether an animal species expresses relevant receptors
or epitopes may affect species selection.
• Similarities of biochemistry and physiology between the species and
humans that are relevant to the limiting toxicities of the therapeutic should
also be considered under class experience.

19. APPLYING SAFETY FACTOR
• In practice, the MRSD for the clinical trial is determined by dividing
the HED derived from the animal NOAEL by the default safety factor of
“10”.
• While a safety factor of 10 can generally be considered adequate for
protection of human subjects participating in initial clinical trials.

21. CONSIDERATION OF THE PHARMACOLOGICALLY ACTIVE
DOSE(PAD)
• If the PAD is from an in vivo study, an HED can be derived from a PAD
estimate by using a body surface area conversion factor (BSA-CF).
This HED value should be compared directly to the MRSD.
• If this pharmacologic HED is lower than the MRSD, it may be appropriate
to decrease the clinical starting dose for scientific reasons.
• Additionally, for certain classes of drugs or biologics, toxicity may arise
from exaggerated pharmacologic effects. The PAD in these cases may be a
more sensitive indicator of potential toxicity than the NOAEL and might
therefore warrant lowering the MRSD.

22. OTHER APPROACHES OF ESTIMATING MRSD
MABL Method
Combined analysis of all of the pharmacology,safety
and efficacy preclinical data.
Similar drug
comparison
method
This may be used when human PK/PD data are available for
drug similar to the one under investigation.
Dosei= Doser NOAELi / NOAELr
Pharmacokinetic
guided approach
Dose = {AUC animal CL human}/Correction factor
A Correction factor is obtained by dividing the clearance of
the chosen species by the predicted human clearance.

23. PK/PD model
guided approach
1)determined PD parameters such as EC50, and
develop the PD models.
2)Human PK parameters, such as CL, bioavailability,
and plasma concentration–time profiles are
predicted.
3)Integrate human PK and PD models to predict
human dose–response relationships.
The PK/PD model- based approach is successful for
monoclonal antibodies, whose PK properties are
usually uniform based on their isotype

24. • For parenteral administration, HED conversion (mg/kg) is also based on body
surface area normalization. The conversion can be made by dividing the NOAEL in
appropriate species by the conversion factor. Guidelines for maximum injection
volumes, by species, site location, and gauge size are summarized in Table.
Injection volume (ml) =Animal weight (kg) × Animal does (mg /kg)/concentration(mg/ml)

25. ? 10 mg/mL, its AED is 62 mg/kg, the rat weight is 250 g and is administered through
intraperitoneal route, and then the injection volume is calculated as:
Injection volume (ml)= 0.25 kg × 62 (mg/kg)/10 (mg/ml) = 1.55 ml
The injection volume observed here (1.55 mL) is well below the maximum injection volume (5–10
mL) for rat through intraperitoneal route and the injection site is lower left
Quadrant.