extrapolation of safety from animals

8/3/2019 Extrapolation of Safety From Animals

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SRINIVAS


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Any NCE tested for safety

Regulatory s consideration

TARGET DISEASE OR CONDITION

ALTERNATIVES AVAILABLE

SAFETY OF THE CLASS


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Primary assumption predictive of effects in humans

EXTRAPOLATION two types

Between species

Effects noted in high or moderate doses to dosage levels thatare at or below dose of interest

Retrospective measurement of data

Even best data, could not predict that next tested

compound will yield a false+ / - or correct data

BIAS most drugs that are highly toxic in animals are

never tested in humans


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OBJECTIVE

Predicting potential toxicity in humans

Clarifying in detail suspected toxicities occurred

previously

TYPES

Dose ranging

Acute /subacute / chronic

Specialized studies ,,,carcinogenicity etc


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Species chosen on basis of

Similarity of ADME to humans

Evolutionary level of animal

Sensitivity of species to medicine Sensitivity of species to demonstrate the effect ,,rats

Economic

Time constraints, practical issues


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Large number of doses problems in interpretation

Large amount of medicine pharmacokinetic issues

saturation of enzymes, etc


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REASONS WHY HIGH DOSE TESTING MAY NOT

MIMICKING HUMAN BA / METABOLISM

Solubility of compound might be limited

Nonlinear kinetics

Metabolites may be toxic that would not occur in lower

doses ( high doses -phenacetin)

Detoxification mechanisms may be depleted or saturated

( acetaminophen)


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Standard test three dose levels,

eg x, 2x, 4x or x, 3x, 9x

Low dose level

To see any adverse events at low dose

May be low as human dose but is chosen as highest dose at

which no toxic effects are anticipated in animals

When dose ranging failed to show toxicity ?

ANS highest dose practical equal dose intervals


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Mid dose level

Multiple of low dose, 2x.,3x

To see some toxic effects

May be minimal effects

High dose level

Four or six fold to low dose

To observe clear toxicity short of death of all animals

Not surprising few deaths


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single-dose toxicity studies in two mammalian species

using both the clinical and a parenteral route of

administration.

However, such information can be obtained from

appropriately conducted dose-escalation studies or

short-duration dose-ranging studies that define an

MTD in the general toxicity test species


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When this acute toxicity information is available from any

study, separate single-dose studies are not recommended.

Studies providing acute toxicity information can be limited

to the clinical route only and such data can be obtained

from non-GLP studies if clinical administration issupported by appropriate GLP repeated-dose toxicity

studies.

Lethality should not be an intended endpoint in studiesassessing acute toxicity.

No LD50


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Generally, in toxicity studies, effects that are potentially

clinically relevant can be adequately characterized using

doses up to the maximum tolerated dose (MTD).

It is not essential to demonstrate the MTD in every study.

Other equally appropriate limiting doses include those thatachieve large exposure multiples or saturation of exposure

or use the maximum feasible dose (MFD).


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Limit doses for acute, subchronic, and chronic toxicity

studies of 1000 mg/kg/day for rodents and non-rodents

are considered appropriate


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Exceptions

In the few situations where a dose of 1000 mg/kg/day does not

result in a mean exposure margin of 10-fold to the clinicalexposure

and the clinical dose exceeds 1 g per day,

then the doses in the toxicity studies should be limited by a 10-

fold exposure margin or a dose of 2000 mg/kg/day or the MFD,whichever is lower.

Doses providing a 50-fold margin of exposure also considered

acceptable as the maximum dose for acute and repeated-dose

toxicity studies in any species.


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The recommended duration - usually related to theduration, therapeutic indication, and scale of the

proposed clinical trial.

In principle, the duration of the animal toxicity studies

conducted in two mammalian species (one nonrodent)

should be equal to or exceed the duration of the humanclinical trials up to the maximum recommended

duration of the repeated dose toxicity studies


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in circumstances where there is a significant cause for

concern for carcinogenic risk should the study results

be submitted to support clinical trials.

Bioassays

In vitro models


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Correlation between animals and humans is variable

Carcinogenicity in mice cannot be predicted from positive

bioassay of rats and vice versa..Dicarlo, 230 bioassays

False + or results------bioassays In vitro ----less valid

Aging rodents have high incidence of tumors than humans,

untreated controls are not true representatives of untreated

humans These animals are overfed and celebate


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Features involved in assessment of relevance of data

Dose of medicine

Type of cancer

number of animals involved Time to occurrence

Epidemiological studies --difficult to determine

carcinogenic potential , if small number of pts are

treated

Animal studies main stay


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detecting chromosomal damage in a mammalian

system(s) should be completed .

A complete battery of tests for genotoxicity should be

completed before initiation of Phase II trials .


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Presumed to be relevant

Over 100 tests available

Invitro ---in vivo animal studies

various combinations are used

Many false + or results from tests such as AMES

Additional evaluations required


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Teratology congenital malformation

Dosing at oogenesis and spermatogenisis

Peri and postnatal studies dosing through last

quarter of pregnancy and lactation


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MEASURES OF BEHAVIOURAL CHANGES IN

ANIMALS BORN TO MOTHERS EXPOSED TO

MEDICINE

Psychological tests

Learning

Short and long term memory

Reproductive

Passive avoidance for shock

Fine motor control

Sight

Social behavior

Extinction


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Type I INTRA SPECIES EFFECTS

Strain, sex , metabolism, genetic breeding, weight age or

other factors

TYPE II INTRA SPECIES EFFECTS

Temperature, housing, humidity, type of diet, amount of

food, light handling, and proximity of animals


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OVERALL DIFFERENCES OBSERVED FOR A

MEDICINE MAY BE

No effect in one species and an effect in another

Opposite effect in two species Different effects in same system in two species

Same effect but different magnitude and time of occurrence


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When Effect at low and high doses? dose related oridiosyncratic?

Observed in other species?

Reversible when medicine stopped? Observed in humans during trial medicine or

concomitant medicine? Difficult to mark causality in such cases

Able to be followed with biomarker?


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Litchfield evaluated six compounds in humans rats and

dogs

ADR would be found if found in both dog and rat

68% of toxic effects in both rats and dogs were found inhumans

79% of toxic effects either in dog or rat were not observed in

humans

Schein et al ,,,,,, Litchfield - overstated by not accountingfalse negatives, which accounted for 68% of toxicity in humans

Fletcher..25% of toxic effects in animals could occur as ADR


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Doses calculated per square meter of surface area can

be compared across species

Eg..

Methotrexate ,,, mouse- 1.5 mg/kg/ day adult human 0.07 mg/kg/ day

mouse3.6 mg/m2/day, adult human 2.7

mg/m2/day


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DURATION OF LONG TERM TESTS

> 3 6 mo meaningful / no use - debatable

DOSES TO USE IN TOXICOLOGY TESTS

Large Vs smallsmall might not be enough

Large saturation

Large new metabolic routes, new metabolites

ASSESSING CLINICAL vs TOXICOLOGICALENDPOINTS

Subjective parameters not possible

Objective anatomical differences


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CIRCADIAN EFFECTS

SPECIES SPECIFICITIES

Differences in absorption, metabolism, protein binding,

intestinal flora, biliary excretion

Species difference in occurrence of tumors

CHOICE OF SPECIES

SHOULD PATHOLOGISTS READ TISSUE SLIDES

BLIND OR UNBLIND


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SHOULD TOXIC MEDICINE BE STUDIED IN HUMANS

False + and results

No alternative?

Reasons for false positive results

Excessive dosage

Creation of metabolites in animals Environmental factors favor the lesion, but these might not occur

in humans at all

Species specific effect

Physiological or anatomical differences

Differences in metabolism / microbial status

Improper housing

Diet of animals

Technical errors


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REASONS FOR FALSE NEGATIVE RESPONSES

Species difference

Poor absorption

Differences in metabolism / elimination Failure to observe subjective signs/ symptoms/ skin reactions

Absence of disease and its pathological effects

Failure to measure the effect found in humans


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When data from two or more species are compared

TYPE I

Compound may effect one aspect of system in one species and

another aspect in other species

Ex;; WBC / RBC

TYPE II

Compound may affect same aspect in opposite way

Ex,, WBC decrease / increase

TYPE III

Compound affects organ which is not present in others


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Degree of riskjustification

Types of extrapolation

2 types

Reterospective

Types of studies

Dose ranging species to consider / large vs small

M3

Special studies , ex carcinogenicity Issues /carcinogenicity - variable

False + /- results


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THANK YOU


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extrapolation of safety from animals

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