Dose extrapolation

1. WELLCOME TO MY
PRESENTATION
Presented By:
Arif Uddin
ID:22215008
Session:2021-22
Department of Pharmacy
Comilla University
Presentation on:
Human Health Risk Assessment
( Dose Extrapolation)

2. WHAT IS EXTRAPOLATION
 Extrapolation can be defined as estimating or arrived at conclusion based
on known facts or conclusions. In preclinical studies we use mathematical
process extrapolation to estimate the conclusion of preclinical drug testing
data to human drugs. This makes us understand how a drug dose & data
can be correlated or estimated to get the same effect in higher mammals.
 In Vitro to In vivo Extrapolation refers to the qualitative or quantitative
transportation of experimental results or observations made in vitro to
predict phenomena in a biological organism.
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3. 1. Linear extrapolation/simple scaling/isometric scaling method: The dose that was
established for one species is applied across all species.
o Advantage: • Simple • Dosage & weight are directly proportional.
o Drawbacks: • 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.
2. Allometric Scaling:
• Allometry, in its broadest sense, describes how the characteristics of living creatures
change with size. The term originally referred to the scaling relationship between the size of
a body part and the size of the body as a whole, as both grow during 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 an allometric exponent.
METHODS OF EXTRAPOLATION OF DATA
Methods of
extrapolation
Linear
extrapolation
Allometric
Scaling
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4. EXTRAPOLATION OF IN VITRO DATA TO PRECLINICAL TO HUMANS
 Estimating the first in human dose (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.
 MABEL( minimum anticipated biological effect level)- it is the
anticipated dose level leading to minimal biological effect level in
humans. In general, MABEL can be used to determine a starting dose
when conventional toxicology testing may not be sufficient to predict
serious adverse reactions in clinical trials.
 NOAEL(No-observed-Adverse–Effect level)- The no observed adverse
effect level is defined as the highest dose where the effects observed in
the treated group do not imply an adverse effect on the subject.
 LOAEL(lowest observed adverse effect level) – it is defined as the
lowest dose where the effects observed in the treated group imply an
adverse effect on the subject.
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5. ESTIMATION OF THE MRSD
Aim of MRSD(maximum recommended starting dose):
• Avoid toxicity at an initial dose
• Dose needs to be high enough to allow reasonably
rapid attainment of phase 1 trial objectives.
Not applicable to :
• Endogenous hormones and proteins
• Vaccines
Limitations:
Does not address dose escalation or maximum allowable
doses in clinical trials
Method of Estimating
the MRSD
NOAEL METHOD
MABEL METHOD
Similar drug
Comparison Method
Pharmacokinetic
Guided Approach
PK/PD Modelling
Guided Approach
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6. 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
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7. NOAEL METHOD
Step 1- No observed adverse Effect Level Determination
• The NOAEL is a generally accepted benchmark for safety when derived from
appropriate 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 should
be considered in the determination of the NOAEL
• Types of findings in nonclinical toxicology studies that can be used to determined
the NOAE:
I. Over toxicity(e.g. Clinical signs, macro & microscopic lesions).
II. Surrogate markers of toxicity( e.g., serum liver enzymes levels).
III. Exaggerated pharmacodynamic effects.
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8. NOAEL METHOD
Step 2: Human Equivalent Dose Calculation
 Correcting for body surface area increase clinical trial safety by resulting in a more conservative starting dose estimate.
 Hence, it was concluded that the approach of converting NOAEL doses to a HED based on body surface area
correction factors 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 conversion for
NOAELs.
 Since surface area varies with surface area correction factors, the conversion factors are therefore dependent on the
weight of the animals in the studies.
 These factors may also be applied when comparing margins for other toxicity endpoints(e.g., reproductivity toxicity &
carcinogenicity) when data for comparison,(i.e., AUCs) are unavailable or are otherwise inappropriate for comparisons.
 HED= Animal NOAEL x (𝑊𝑎𝑛𝑖𝑚𝑎𝑙 /𝑊𝐻𝑢𝑚𝑎𝑛 ) (1−𝑏)
 Conventionally, for an mg/m2 normalization b should be 0.67, but studies have shown that MTDs(maximum tolerated
dose) scale best across species when b= 0.75
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9. NOAEL METHOD
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10. NOAEL METHOD
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:
I. Difference 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.
II. 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. E.g.- in the nonclinical safety assessment of the phosphorothioate antisense drug, the monkey is
considered the most appropriate species because monkeys experience the same dose-limiting toxicity as humans whereas rodents do
not.
III. 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.
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11. NOAEL METHOD
Step 4: Application of safety factor: A safety factor is applied in order to provide a margin of safety for the
protection of human subjects receiving the initial clinical dose.
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, comparing it to the PAD derived from appropriate
pharmacodynamics models may be valuable.
• If the PAD is from an in vivo study, a 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.
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12. PROCESS OF EVALUATION OF DATA
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13. REFERENCE
1. https://www.slideshare.net/SushobhanRoy4/extrapolationpptx
2. https://www.slideshare.net/ARSHIKHANAM4/extrapolation-of-in-
vitro-data-to-preclinical-andpptx
3. https://www.slideshare.net/Prakharvarshney27/extrapolation-of-in-vitro-
data-to-preclinical
4. https://www.ncbi.nlm.nih.gov/books/NBK218076/
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