One of the most important considerations before starting human studies

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FIRST IN HUMAN DOSE

2. INTRODUCTION
• 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.
• It is an important parameter in the FIH clinical trials, since a high starting
dose may cause serious toxicity in volunteers, while a low starting dose
could prolong the dose escalation/optimisation, leading to unnecessary
delay in the clinical programs.
• 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.
• The process of calculating the MRSD should begin after the toxicity data
have been analyzed.

3. 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, not just adverse
ones, although in some cases the two might be identical.
5) LOWEST OBSERVED ADVERSE EFFECT LEVEL (LOAEL): The lowest dose that
produces adverse effects.
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

6. MAXIMUM RECOMMENDED STARTING DOSE
(MRSD)
Aim of MSRD:
• Avoid toxicity at initial dose
• Dose needs to be high enough to allow reasonably rapid attainment of phase
I trial objectives.
Not applicable to:
• Endogenous hormones and proteins (i.e. recombinant clotting factors) used
at physiological concentrations
• Vaccines
Limitations:
• Does not address dose escalation or maximum allowable doses in clinical
trials

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

8. 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.
• This approach works well with new molecules that act on established targets
and/or have the pharmacology that is more or less understood.
• 5 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

9. STEP 1: NO OBSERVED ADVERSE
EFFECT LEVEL DETERMINATION
 The NOAEL is a generally accepted benchmark for safety when derived
from appropriate animal studies.
 The available animal toxicology data is reviewed and evaluated so that a
NOAEL can be determined for each study.
 While reviewing the animal toxicology data, the adverse effects that are
statistically significant and adverse effects that may be clinically
significant (even if they are not statistically significant) should be
considered in the determination of the NOAEL.

10. TYPES OF FINDINGS IN NONCLINICAL TOXICOLOGY STUDIES THAT
CAN BE USED TO DETERMINE THE NOAEL
 Overt toxicity (e.g., clinical signs, macro- and microscopic lesions)
 Surrogate markers of toxicity (e.g., serum liver enzyme levels) and
 Exaggerated pharmacodynamic effects.
 As a general rule, an adverse effect observed in nonclinical toxicology
studies used to define a NOAEL for the purpose of dose-setting 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:
 Bioavailability, metabolite profile, and plasma drug levels associated with
toxicity may influence the choice of the NOAEL.
 Ex: Saturation of drug absorption at a dose that produces no toxicity. In
this case, the lowest saturating dose, not the highest (non-toxic) dose,
should be used for calculating the HED.

11. STEP 2: HUMAN EQUIVALENT DOSE CALCULATION
Conversion Based on Body Surface Area
• 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.
• Toxic endpoints for therapeutics administered systemically to animals, such as
the MTD or NOAEL, are usually assumed to scale well (doses scaled 1:1)
between species when doses are normalized to body surface area (mg/m2).
• The basis for this assumption: 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.

12. STEP 2: HUMAN EQUIVALENT DOSE CALCULATION
• Correcting for body surface area increases clinical trial safety by resulting in a
more conservative starting dose estimate.
• 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.
CONVERSION FACTORS:
• These are recommended as the standard values to be used for interspecies
dose conversions for NOAELs.
• Since surface area varies with W0.67, the conversion factors are therefore
dependent on the weight of the animals in the studies.
• These factors may also be applied when comparing safety margins for other
toxicity endpoints (e.g., reproductive toxicity and carcinogenicity) when data
for comparison, (i.e., AUCs) are unavailable or are otherwise inappropriate for
comparison.

13. STEP 2: HUMAN EQUIVALENT DOSE CALCULATION
 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)0.33 or (Wanimal/Whuman)0.25 to assess the effect on starting
dose selection of using b = 0.75 instead of b = 0.67.
 However, converting doses based on an exponent of 0.75 would lead to
higher, more aggressive and potentially more dangerous starting doses.
• Nonetheless, use of a different dose normalization approach, such as directly
equating the human dose to the NOAEL in mg/kg, may be appropriate in some
circumstances.

14. STEP 2: HUMAN EQUIVALENT DOSE
CALCULATION

15. 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.
 Circumstances for using mg/kg for calculating HED
1. NOAELs occur at a similar mg/kg dose across test species (for the studies
with a given dosing regimen relevant to the proposed initial clinical trial).
2. When toxicity in humans (for a particular class) is dependent on an
exposure parameter that is highly correlated across species with dose on a
mg/kg basis.
Ex: Complement activation by systemically administered antisense
oligonucleotides in humans is believed to be dependent upon Cmax. For
some antisense drugs, the Cmax correlates across nonclinical species with
mg/kg dose and in such instances mg/kg scaling would be justified.
Also there is a robust correlation between plasma drug levels (Cmax and
AUC) and dose in mg/kg.
3. Other pharmacologic and toxicologic endpoints also scale between species
by mg/kg for the therapeutic. Examples of such endpoints include the
MTD, lowest lethal dose, and the pharmacologically active dose.

16. BASIS FOR USING MG/KG CONVERSIONS
4. Therapeutics administered by alternative routes (e.g., topical, intranasal,
subcutaneous, intramuscular) for which the dose is limited by local toxicities.
Such therapeutics should be normalized to concentration (e.g., mg/area of
application) or amount of drug (mg) at the application site.
5. Therapeutics administered into anatomical compartments that have little
subsequent distribution outside of the compartment.
Ex: Intrathecal, Intravesical, Intraocular, or Intrapleural administration.
Such therapeutics should be normalized between species according to the
compartmental volumes and concentrations of the therapeutic.
6. Biological products administered intravascularly with MW > 100,000 daltons.
Such therapeutics should be normalized to mg/kg.
mg/m2 = km × mg/kg
where km = 100/K × W0.33 where K is a value unique to each species
(Freireich et al. 1966)

17. CONVERSION OF ANIMAL DOSES TO HUMAN
EQUIVALENT DOSES BASED ON BODY SURFACE
AREA

18. STEP 3: MOST APPROPRIATE SPECIES
SELECTION
 HED should be chosen from the most appropriate species.
 Most sensitive species (i.e., the species in which the lowest HED can be
identified).
 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.
When determining the MRSD for the first dose of a new therapeutic in
humans, the ADME parameters will not be known. Comparative
metabolism data, however, might be available based on in vitro studies.
These data are particularly relevant when there are marked differences in
both the in vivo metabolite profiles and HEDs in animals.

19. MOST APPROPRIATE SPECIES
SELECTION
 (2) Class experience that may indicate a particular animal model is more
predictive of human toxicity.
Class experience implies that previous studies have demonstrated that a
particular animal model is more appropriate for the assessment of safety
for a particular class of therapeutics.
Selection of the most appropriate species for certain biological products
involves consideration of various factors unique to these products.
(a) Factors such as whether an animal species expresses relevant receptors
or epitopes may affect species selection.
Ex: In the nonclinical safety assessment of the phosphorothioate antisense
drugs, the monkey is considered the most appropriate species because
monkeys experience the same dose limiting toxicity as humans (e.g.,
complement activation) whereas rodents do not.

20. MOST APPROPRIATE SPECIES
SELECTION
 For this class of therapeutics, the MRSD would be based on the HED for the
NOAEL in monkeys regardless of whether it was lower than that in rodents,
unless unique dose limiting toxicities were observed with the new antisense
compound in the rodent species.
(b) 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.
 If a species is the most sensitive but has differences in physiology compared
to humans, it may not be the most appropriate species for selecting the
MRSD.
 (3) Limited biological cross-species pharmacologic reactivity of the
therapeutic. This is especially important for biological therapeutics as many
are human proteins that bind to human or non-human primate targets.

21. STEP 4: APPLICATION OF SAFETY FACTOR
 A safety factor is applied in order to provide a margin of safety for
protection of human subjects receiving the initial clinical dose.
 This safety factor allows for variability in extrapolating from animal toxicity
studies to studies in humans resulting from:
(1) Uncertainties due to enhanced sensitivity to pharmacologic activity in
humans versus animals
(2) Difficulties in detecting certain toxicities in animals (e.g., headache,
myalgias, mental disturbances)
(3) Differences in receptor densities or affinities
(4) Unexpected toxicities and
(5) Interspecies differences in ADME of the therapeutic.
 These differences can be accommodated by lowering the human starting
dose from the HED of the selected species NOAEL.

22. 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, this
safety factor may not be appropriate for all cases.
 The safety factor should be raised when there is reason for increased
concern, and lowered when concern is reduced because of available data
that provide added assurance of safety.

23. INCREASING THE SAFETY FACTOR
 Steep dose response curve.
 Severe toxicities.
 Nonmonitorable toxicity
 Toxicities without premonitory signs.
 Variable bioavailability.
 Irreversible toxicity
 Unexplained mortality
Large variability in doses or AUC
levels eliciting effect.
Nonlinear pharmacokinetics.
Questionable study design or
conduct
Inadequate dose-response data.
Novel therapeutic targets.
Animal models with limited utility.

24. DECREASING THE SAFETY FACTOR
 When the toxicologic testing in these cases is of the highest caliber in both
conduct and design.
 When the candidate therapeutics are members of a well-characterized
class.
 When within the class, the therapeutics are administered by the same
route, schedule, and duration of administration; have a similar metabolic
profile and bioavailability; and have similar toxicity profiles across all the
species tested including humans.
 When toxicities produced by the therapeutic are easily monitored,
reversible, predictable, and exhibit a moderate-to-shallow dose-response
relationship with toxicities that are consistent across the tested species
(both qualitatively and with respect to appropriately scaled dose and
exposure).
 When the NOAEL was determined based on toxicity studies of longer
duration compared to the proposed clinical schedule in healthy volunteers.

25. STEP 5: CONSIDERATION OF THE
PHARMACOLOGICALLY ACTIVE DOSE(PAD)
 Selection of a PAD depends upon many factors and differs markedly among
pharmacological drug classes and clinical indications.
 Once the MRSD has been determined, it may be of value to compare it to
the PAD derived from appropriate pharmacodynamic models.
 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.

26. STARTING DOSE CALCULATION
IT IS ALWAYS ACCEPTABLE (FROM
A SAFETY PERSPECTIVE) TO USE A
CLINICAL START DOSE LOWER
THAN THE MRSD.

27. IS NOAEL APPROACH THE FOOLPROOF
METHOD FOR CALCULATING FIH DOSE?
• NOAEL approach= safety window based on
toxicological threshold
• TRAGIC TRIAL OF TGN1412
• TGN1412 : A novel CD28 super-agonist antibody immunomodulator
• Developed by TeGenero Immuno Therapeutics,London, tested by
Parexel and manufactured by Boehringer-Ingelheim.
• Intended for the treatment of B cell chronic lymphocytic leukemia (B-CLL)
and rheumatoid arthritis.
• Caused cytokine storm.
• Dose in humans was 1/160 of the NOAEL in monkeys, so it was well within
accepted safety margins.

28. COULD THIS TOXICITY HAVE BEEN
PREDICTED?
• No evidence of contamination of the product.
• Conduct of the trial appeared to have followed the protocol, e.g., no
dosing errors.
• Nothing in the preclinical data that predicted the overwhelming systemic
reaction to the antibody.
 Initial dose 0.1 mg/kg would achieve plasma level of ~16nM compared
with binding affinity of 2nM. 8X the binding affinity of “super agonist”
might result in 90% CD28 receptor binding on first dose.
 This occupancy is considered sufficient for an antagonist but too high for
FIH with agonist. If starting dose was established using pharmacological
principles, the dose might have been started 100X lower.

29. DUFF REPORT RECOMMENDATIONS
SELECTION OF THE FIH DOSE FOR CLINICAL TRIAL
 The EMEA proposed for micro dosing a safety factor of 1/100th of the dose
calculated to yield a pharmacologic effect, on a mg/m2 basis, and suggested
that such a dose should be 1/1000th of the minimal toxic effect dose (MTED)
from a single-dose toxicology study.
 Special consideration should be given to new agents for which the primary
pharmacological action, for the proposed therapeutic effect, cannot be
demonstrated in an animal model.
 A broader approach to dose calculation, beyond reliance on NOEL or NOAEL in
animal studies, should be taken.

30. DUFF REPORT FOR FIH DOSE SELECTION
 The calculation of starting dose should utilize all relevant information. Factors
to be taken into account include
 The novelty of the agent
 Biological potency and its mechanism of action
 Degree of species-specificity of the agent
 Dose-response curves of biological effects in human and animal cells
 Dose-response data from in vivo animal studies
 Pharmacokinetic and pharmacodynamic modeling
 Calculation of target occupancy versus concentration
 Calculated exposure of targets or target cells in humans in vivo.
 If different methods give different estimates of a safe dose in humans, the
lowest value should be taken as the starting point in first-in-man trials and a
margin of safety introduced in calculation of the actual starting doses in man.

31. THE MABEL APPROACH FOR DOSE SELECTION
• This is an improved approach to dose selection through the combined
analysis of all of the pharmacology, safety and efficacy preclinical data.
• The main objective of the new process is to define a starting dose that is
expected to result in a minimum anticipated biological effect level
(MABEL), particularly for investigational medicinal products where risk
factors were identified in
(1) Mode of action
(2) Nature of the target and
(3) Relevance of animal species and models.

32. THE MABEL APPROACH FOR DOSE SELECTION
(1) The mode of action :
• This refers to the knowledge on the nature and intensity of the effect of the
medicinal product on the specific target and non-targets and subsequent
mechanisms.
• Certain modes of action have been identified to require special attention:
 Targets that have pleiotropic effects or are ubiquitously expressed (e.g., as
often occur in the immune system)
 Targets that have a biological cascade or cytokine release, including those
leading to an amplification of an effect that might not be sufficiently
controlled by a physiological feedback mechanisms (e.g., Monoclonal
antibodies against the T cell targets).

33. (2) The nature of the target
• This may include information on the structure, tissue distribution, cell
specificity, disease specificity, regulation, polymorphisms, level of expression,
and biological function of the human target, including downstream effects,
and how it might vary between individuals in different populations of healthy
subjects and patients.
(3) The relevance of animal models.
• The available animal species should be compared to humans taking into
account the target, its structural homology, distribution, signal transduction
pathways and the nature of pharmacological effects.
• Where the available animal species/models or surrogates are perceived to be
of questionable relevance for thorough investigation of the pharmacological
and toxicological effects of the medicinal product, this should be considered as
adding to the risk.
• The risk assessment should be performed on a ‘‘case-by-case’’ basis and that
a ‘‘weight-of-evidence’’ approach should be used.

34. • The calculation of MABEL should use all in vitro and in vivo information
available from PK/PD, which may include the following:
(1) Target binding and receptor occupancy studies in vitro in target cells from
human and the relevant animal species
(2) Concentration-response curves in vitro in target cells from human and the
relevant animal species and dose/exposure-response in vivo in the relevant
animal species
(3) Exposures at pharmacological doses in the relevant animal species
• To further limit the potential for adverse reactions in humans, a safety
factor may be applied in the calculation of the first dose in humans from
MABEL.
• In cases where the methods of calculation (e.g. NOAEL, MABEL) give
different estimations of the first dose in man, the lowest value should be
used.

35. SIMILAR DRUG COMPARISON APPROACH
• This may be used when human PK/PD data are available for a drug similar
to the one under investigation.
• The dose of the investigated drug can be calculated from the dose of the
reference drug:
Dosei = Doser NOAELi / NOAELr
• The dose obtained is usually corrected by an arbitrary safety factor to
accommodate uncertainty.

36. PHARMACOKINETIC-GUIDED APPROACH
• In this approach, the NOAEL and corresponding AUC in several animal
species are determined.
• The species that results the lowest NOAEL is used as the index species for
scaling.
• The starting oral dose can be calculated as follows:
Dose = CL AUC / F
Dose = Clhuman Css Dosing Interval /F
Dose = {AUCanimal CLhuman} / Correction factor
A Correction factor
is obtained by
dividing the
clearance of the
chosen species
by the predicted
human clearance.

37. • A few assumptions are made with pharmacokinetic-guided approaches:
(1) Only the parent compound is active, and
(2) The drug shows equal pharmacological activity or toxicity in human and
nonhuman animal species at equal plasma concentrations.
• This results in the inability to account for interspecies differences in
pharmacodynamics, which are extremely important to identify prior to
phase I trials.

38. PK/PD MODEL-GUIDED APPROACH
• To avoid inaccuracy caused by interspecies differences in exposure–
response relationships, PK/PD modeling has been utilized to estimate the
FIH dose.
• The human PK/PD profile could be projected using animal data from a
single species.
Estimation of human doses using a four-step approach (Lowe et al):
1) First step: Set up the concentration–effect relationships to identify
biomarkers, determined PD parameters such as EC50, and develop the
PD models.
2) Second step: Identify the interspecies differences in the concentration–
response profiles, for both desired and adverse effects. This includes
differences in tissue distribution, tissue and plasma protein binding,
blood cell binding, and target receptor occupancy.

39. 3) Third step: Human PK parameters, such as CL, bioavailability, and plasma
concentration–time profiles are predicted.
4) Fourth step: Integrate human PK and PD models to predict human dose–
response relationships, which involves further two approaches.
A) Threshold model: A dosing regimen is designed to keep drug
concentrations above the threshold of efficacy (e.g.,EC50) but below
the threshold of adverse effects.
B) PK/PD model: To simulate the dose–exposure–response–time profiles,
which could incorporate the complex PD models.
 The PK/PD model- based approach is successful for monoclonal antibodies,
whose PK properties are usually uniform based on their isotype.

40. • The receptor occupancy (RO), which can be measured by in vitro
experiments, may be used as the biomarker for the human PK/PD model.
• When estimating the starting dose the RO value is recommended to be low
for an agonist and high for an antagonist.

41. METHOD APPLICABILITY ADVANTAGES DISADVANTAGES
NOAEL To drugs administered
orally, intranasally, SC, or
IM and the dose is
limited by local toxicities.
Proteins administered
intravascularly with MW
>100 kDa
Good safety record for
small molecule drugs;
easy to use
Arbitrary safety factor
makes the approach
very conservative.
Neglect the
interspecies
differences in
pharmacology, such as
binding affinity and
potency
MABEL To both biotherapeutics
and small molecule
chemical entities
Based on pharmacologic
knowledge rather than
an empirical factor
Requires extensive
mechanistic data
SIMILAR DRUG
COMPARISON
Human PK data are
available for a drug
similar to the one under
investigation
Easy to use; very limited
data are required
Only applicable to
very limited drug
candidates

42. METHOD APPLICABILITY ADVANTAGES DISADVANTAGES
PK-GUIDED
APPROACH
Human PK parameters
predicted from
preclinical data with a
reasonable accuracy.
Based on pharmacokinetic
properties rather than
an empirical factor
Neglect interspecies
differences in
pharmacodynamics;
depends on the
prediction
accuracy of human PK
parameters
PK/PD
MODELING-
GUIDED
APPROACH
Human dose–exposure–
response relationships are
simulated by a mathematic
model
Interspecies differences in
both PK and PD are
considered; reduce the
reliance on empirical
safety factors
A lot of efforts are
required
to establish and
validate
PK/PD models

43.  Adequate preclinical in vivo toxicological testing may not be possible due
to lack of cross-reactivity in commonly accepted toxicological test species
such as rats and dogs.
 Even for cross-reactive MABs, due to differences in the pharmacology
between test species and humans, the NOAEL obtained in test species may
not be relevant to human testing in some cases.
 Furthermore, toxicity for many biologics is typically due to exaggerated
pharmacology
 Predicting human pharmacological response from preclinical data also
presents unique challenges in the case of biologics compared with small
molecules.
 Therefore, characterizing the preclinical pharmacological response is
critical to understanding potential clinical safety implications for these
compounds.
POINTS TO CONSIDER IN THE SELECTION
OF FIH DOSES FOR BIOLOGICS

44. INTERACTION OF MABs WITH THEIR TARGET IS, DIFFERS FROM
THAT OF SMALL MOLECULES:
 Because of their high affinity, MABs are typically dosed at equal molar
ratios to their targets.
 The on- and off-rates of MABs at their receptors are, slower than those of
small molecules.
 Binding of target by MAB may change the natural kinetics of the receptor,
e.g. trigger internalization or stabilization of the receptor.
 Due to the relatively slow distribution to the site of action and target
mediated elimination of MABs, unbound MAB concentrations at the
biophase after single doses and at steady state may be one to three orders
of magnitude below unbound MAB concentrations in plasma.

45.  Because of these characteristics, simple equilibrium calculations of in vivo
RO based on affinity that are applied for many small molecules may not be
applicable for MAB therapeutics.
 Toxic effects in humans are likely to be sustained for long durations due to
the long half-lives
 Selection of too low a starting dose could substantially increase the
duration of clinical studies, increasing the cost and duration of
development with limited additional safety benefit.
 Rational selection of starting doses is of added importance for MAB
programmes

46. PROPOSED APPROACH BY REGULATORS
(a) Obtain the predicted human dose–
response for all measured biological
effects. in vivo biomarker studies,
receptor binding affinity and occupancy
experiments, antibody-dependant cell
cytotoxicity (ADCC) assay, PK–PD
experiments
(b) Select the dose that would result in minimal biological activity – MABEL dose.
b-agonists produce maximal bronchodilation at <5% RO, and ERAs produce maximum
effect at 20–30% RO, antagonists require generally higher RO to exert their effect: anti-IgE
and anti-CCR5 therapeutics are clinically effective at >90% and >99% RO, respectively.
Therefore, based on target-mediated effects, a starting dose targeting 50% RO could be
considered a MABEL dose for a CCR5 antagonist, whereas <3% RO is more appropriate for an
ERA.
Hence, the choice of starting dose should take into consideration all available information
on the relationship between RO and biological effect for the relevant class of compounds.
(c) Obtain the NOAEL from toxicological testing