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SRINIVAS

Any NCE tested for safety Regulatory s consideration TARGET DISEASE OR CONDITION ALTERNATIVES AVAILABLE SAFETY OF THE CLASS

Primary assumption predictive of effects in humans EXTRAPOLATION two types


Between species Effects noted in high or moderate doses to dosage levels that are 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

OBJECTIVE Predicting potential toxicity in humans Clarifying in detail suspected toxicities occurred previously TYPES Dose ranging Acute /subacute / chronic Specialized studies ,,,carcinogenicity etc

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

Large number of doses problems in interpretation Large amount of medicine pharmacokinetic issues saturation of enzymes, etc

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)

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

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

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

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 is supported by appropriate GLP repeated-dose toxicity studies.
Lethality should not be an intended endpoint in studies assessing acute toxicity. No LD50

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 that achieve large exposure multiples or saturation of exposure or use the maximum feasible dose (MFD).

Limit doses for acute, subchronic, and chronic toxicity studies of 1000 mg/kg/day for rodents and non-rodents are considered appropriate

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 clinical exposure and the clinical dose exceeds 1 g per day, then the doses in the toxicity studies should be limited by a 10fold 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.

The recommended duration - usually related to the duration, 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 human clinical trials up to the maximum recommended duration of the repeated dose toxicity studies

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

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

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

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 .

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

Teratology congenital malformation Dosing at oogenesis and spermatogenisis Peri and postnatal studies dosing through last quarter of pregnancy and lactation

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

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

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

When Effect at low and high doses? dose related or


idiosyncratic?

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?

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

Schein et al ,,,,,, Litchfield - overstated by not accounting


false negatives, which accounted for 68% of toxicity in humans

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

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

DURATION OF LONG TERM TESTS


> 3 6 mo meaningful / no use - debatable

DOSES TO USE IN TOXICOLOGY TESTS


Large Vs small small might not be enough Large saturation Large new metabolic routes, new metabolites

ASSESSING CLINICAL vs TOXICOLOGICAL ENDPOINTS


Subjective parameters not possible Objective anatomical differences

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

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

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

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

Degree of risk justification Types of extrapolation


2 types Reterospective Dose ranging species to consider / large vs small M3 Special studies , ex carcinogenicity

Types of studies

Issues /carcinogenicity - variable False + /- results

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