Toxicology in Pre-clinical Development I

What considerations need to be taken into account when deciding whether a drug should be marketed or dropped from development?

Shareholders, investment in new drug development, drug not financially viable (no profit, using small sample size), safety and finance

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Given the risks associated with paracetamol, would it pass a modern safety evaluation?

High doses of paracetamol can cause liver impairment. Safety put in place, limited supply e.g. 16 paracetamol tablets (supermarket), 32 paracetamol tablets (pharmacy), info about dose (therapeutic window)

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What are the major reasons why drugs react differently in the elderly?

Changes in renal and hepatic function. Reduced elimination. Accumulation of drug

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Why is a drug safety evaluation needed? (1)

All substances are poisons, the right dose differentiates a poison and a remedy. Doctors put drugs of which they know little into our bodies of which they know less to cure diseases of which they know little at all

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Why is a drug safety evaluation needed? (2)

There are no safe drugs, only safe ways of using them

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Describe features of thalidomide (1)

Distaval, used for morning sickness during pregnancy, mild sedative. Seemed relatively safe, low risk of overdose. Later found to cause peripheral neuropathy

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Describe features of thalidomide (2)

Taken by a pregnant woman at a certain point in gestation (day 24-33) – led to abnormalities in foetus (interference with blood vessels). Shortened arms (phocomelia), missing arms (amelia)

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Describe features of species specificity of thalidomide toxicity (1)

No effect in rats. Limb defects only occur in some rabbits. Occurs in monkeys (primates)

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Describe features of species specificity of thalidomide toxicity (2)

Abnormalities in foetus doesn’t occur in rodents (limb defects seen in primates). Important to choose correct animal for study. Just because abnormalities are not seen in rodents, doesn’t mean it won’t appear in humans

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Describe features of the Committee on Safety of Medicines

Set up after the thalidomide tragedy. Part of MHRA. Drug licensing. Inform public about safety alerts. Also deal with the regulation of medical devices e.g. crutches, plastic surgery items etc. HCPs/public can report ADRs

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What are the fundamentals for toxicity? (1)

All substances have the potential to cause toxicity. Only the dose distinguishes harmless effects from toxicity. Toxic effects often follow a dose response curve

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What are the fundamentals for toxicity? (2)

Allows the prediction of probability of toxic effects at one dose from knowledge of toxic effects at other doses

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Describe features of the dose response curve

Sigmoid shape, able to predict toxicity at any dose (determined % of patients affected). Log concentration against % response. Curve - further to the right, less toxicity

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Describe features of the toxicity constants (1)

NOAEL (No Observed Adverse Effect Level - below this level the drug is safe) – not all drugs have this, highly dependent upon testing conditions

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Describe features of the toxicity constants (2)

NOAEL is the concentration below at which no adverse effect is noted. Some compounds demonstrate no NOAEL - no safe dose

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Describe features of the toxicity constants (3)

LD50 – lethal dose 50 (concentration which causes 50% reduction in % response). TD50 – toxic dose 50. Lethality – specific adverse reaction (death – most toxic reaction). Toxicity e.g. drugs causing deafness (reversible)

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Describe features of the toxicity constants (4)

Can have dose-response curves for toxicity and effective doses. ED50 – concentration which causes 50% effectiveness. ED, TD, LD curves (order from left to right).

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Describe features of the toxicity constants (5)

Use curves to compare drugs/calculate constants for drugs. Variations in sigmoid shape of curve (different profile, different ED, TD, LD values)

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How do you calculate the therapeutic index? (1)

TD50/ED50 or LD50/ED50. Compares toxicity which pharmacological efficacy. The higher the TI, the safer the drug

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How do you calculate the therapeutic index? (2)

Therapeutic index (no units, ratio) – compares TD50 or LD50 to ED50 (determines distance of curves from other drugs/constants). Higher therapeutic index – further away the curve is from ED (wider therapeutic index, safer). TI always greater than 1

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How do you calculate the margin of safety? (1)

TD1/ED99 or LD1/ED99. Take lowest dose which causes toxicity, compare to highest dose for efficacy. Higher MS, safer drug (>1, no curve overlap). No effective dose that kills (doesn’t cause toxicity)

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How do you calculate the margin of safety? (2)

MS <1 (overlap between top of efficacious curve and bottom with toxicity) – at some doses which are effective may also cause toxicity

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How do you calculate the margin of safety? (3)

MS is more critical than TI. Compares lowest dose showing toxicity with highest dose showing efficacy. Higher MS, safer drug. Much more stringent than TI

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Describe the evaluation of toxicity (1)

Safety evaluation is often, but not always, carried out in experimental animals. Some information is gained from in-vitro experiments (early screening of potential drugs in isolated cells, liver/target cells, check toxicity)

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Describe the evaluation of toxicity (2)

If they pass in-vitro testing - use drug in experimental/animal model. Some information is gained from human (clinical) trials. If drug is already licensed, don't need to repeat toxicology studies (ethics)

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Why do safety evaluation/toxicology studies on drugs? (1)

Guidance on dose levels for clinical trials. Determine margin of safety. Prevent serious irreversible toxicity (in clinical trials and in clinical use). Provide data for management of overdoses

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Why do safety evaluation/toxicology studies on drugs? (2)

Identification of target organs for clinical surveillance. Information on toxicity and relationship between blood level, dose and toxicity. Check for hepatic impairment, identify target organs, information about PK

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Outline the drug discovery pipeline (1)

Target identification. Target assay construction and screening. Target validation hits-to-leads medicinal safety. Phase I (safety), phase II (efficacy, safety), phase III (efficacy, safety), FDA review and approval

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Outline the drug discovery pipeline (2)

In-vitro safety screening takes place within a third of the drug discovery process

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Describe features of drug safety evaluation

Drug safety evaluation is part of drug development. Efficacy, dosing, risk/benefit, cost/performance. Highly regulated and involves many people. Expensive ($300m+)

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What are the pharmacogenetic implications? (1)

What enzymes are involved in key metabolic pathways? Does clearance depend solely upon a single rate-limiting enzyme? Is that enzyme subject to genetic or environmental variation in activity?

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What are the pharmacogenetic implications? (2)

Are there any significant potentials for drug-drug and drug-diet interactions? Continue development? What restrictions may have to be put in place?

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State features of a drug safety evaluation

Test according to a standard protocol. Look for everything, hope for nothing. Treat one group with toxic doses. Record toxicity. Determine NOAEL dose. Determine toxicity constants

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Describe the development of new drugs

Use in man is desirable as soon as possible to find out if the drug works and if humans tolerate drug. But must have some knowledge of effects in animals. Evaluation of effects in animals at any stage may preclude further development

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What are the questions/information required before toxicity studies? (1)

Use of drug. Physicochemical properties - lipid solubility, state, corrosive, volatile, acid/base (absorption). Is it a novel drug? Other/existing toxicity data. QSAR

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What are the questions/information required before toxicity studies? (2)

Single or repeat dose drug. Age group of patient. Exposure of pregnant women. Route of administration. Pharmacological action. Likely dose

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State features of preclinical trials

Safety pharmacology (acute doses). Genotoxicity (in-vitro mutagenicity, determine if drug mutates DNA). Single dose toxicity. Repeat dose toxicity. Local tolerance/irritant effects (changing injection sites, resistance to drug/using same site)

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What are the three different types of toxicity?

Biochemical (change in enzyme, solute levels). Functional (change in system such as immune or blood pressure). Structural (gross or microscopic pathological change)

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What are the other tests carried out during a drug safety evaluation?

Reproductive, mutagenicity and carcinogenicity (determine if the drug causes cancer)

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What are the specialised tests carried out during a drug evaluation?

Ocular, otoxicity, skin sensitisation, behavioural

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What are the three basic types of study required for the safety evaluation of a chemical?

Acute, sub-chronic and chronic

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Describe features of an acute study

Defines dose response. Single doses in rodent. Monitor animals for 7 days (clinical signs, body weight, food/water intake). Post mortem (organ weights, gross/microscopic pathology)

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Describe features of a sub-chronic study (1)

3 doses (including intended dose). Repeat (daily) doses in rodent and non-rodent for 28-90 days via expected route. Look at - clinical signs, clinical chemistry, body weight, food/water intake. Post mortem - organ weights, gross/microscopic pathology

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Describe features of a sub-chronic study (2)

Higher doses used, determine accumulative effect

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Describe features of a chronic study

3 doses (including intended dose). Repeat (daily) doses in rodent and non-rodent for 6 months plus via expected route. Same evaluations as sub-chronic tests. Can detect all types of changes. See more results in chronic study

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What are the toxicologists looking for? (1)

Gross clinical signs of toxicity (appearance, body weight changes in animals). Gross pathology (organ weight changes, appearance/tumours/atrophy). Histopathological changes (light microscopy). Ultrastructural changes (electron microscopy)

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What are the toxicologists looking for? (2)

Check for liver damage - first pass metabolism, first organ to be damaged. Aim for 3Rs (reduction, replacement, refinement, use of organoids, unethical to use too few animals/poor experimental plan/no clear reason, mainly male rodents used)

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What are the toxicologists looking for? (3)

Sub-chronic and chronic tests - look at clinical chemistry (biochemical changes in enzyme or metabolite levels reflecting damage or dysfunction), haematology (loss of blood cells)

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Describe features of clinical chemistry and pathology (1)

Blood flows through all tissues and therefore reflects their status. Repeatedly monitored through toxicity tests - liver damage and dysfunction, cell contents may leak into the blood e.g. alanine aminotransferase for liver damage

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Describe features of clinical chemistry and pathology (2)

Organ dysfunction (albumin decreased, intermediary metabolism altered)

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What are the markers of liver dysfunction?

Serum plasma transaminases (ALT and AST) elevated. Reduced serum albumin. Elevated serum bilirubin. Increased clotting time. Reduced serum glucose

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What are the markers of kidney dysfunction?

Urine constituents (markers most commonly used for kidney dysfunction). Increased urine volume. Specific enzymes (gamma-glutamyltranspeptidase increased). Metabolites (increased amino acids/glucose, reduced urea)

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Why do pre-clinical toxicology studies? (1)

Cannot ethically/legally expose humans to chemicals (potential drugs). Animals are still the best surrogates for humans. Large database. Vast majority of chemicals toxic in humans have similar effect/mechanism in animals

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Why do pre-clinical toxicology studies? (2)

Almost all known human carcinogens also cause tumours in rodents. Pharmacogenetic variation not modelled - animals are from inbred strains

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Why not use in-vitro techniques? (1)

Often poor correlation with in-vivo data. Limited availability of normal human material. Problems of extrapolation to human in-vivo. Only one tissue exposed, may not be the target organ

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Why not use in-vitro techniques? (2)

Toxicity may require complex interactions - cell, tissues, organs, hormones

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Why do drugs fail?

Poor absorption/inactivation (animal studies), systemic toxicity, poor absorption/inactivation (phase I), systemic toxicity (phase I), ineffective/toxic (phase II), ineffective/toxic (phase III), unexpected adverse effects (phase IV)

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Toxicology in Pre-clinical Development I

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