4PY019 IDM Safety Pharmacology and Toxicology Study Guide PDF

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Download 4PY019 IDM Safety Pharmacology and Toxicology Study Guide PDF

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4PY019

Safety Pharmacology and Toxicology In S

Student Study Guide

Facilitators

Required References

Names:

Required:

Dr Mark Hewitt

This study pack

([email protected]) Optional: Dr Colin Brown

An Introduction to Pharmacology – M.A. Hollinger

([email protected])

An introduction to Toxicology – P.C. Burcham Rang and Dale’s Pharmacology References at end of study pack

Learning Outcomes

This study pack considers a number of important topics relating to safety pharmacology and the toxicity of drug substances.

On completion of this topic, you should be able to:

• • • • • • • •

Explain what is meant by safety pharmacology Understand the structure of a typical safety pharmacology program Understand what is meant by drug toxicity Explain common target organs of toxicity Explain what is meant by adverse drug reactions Understand the general (and more specific) mechanisms of toxicity Understand how toxicity can be measured and screened for Appreciate that toxicity can sometimes be predicted

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4PY019 Contents

What is Safety Pharmacology?..............................................................................................3 Rationale................................................................................................................................4 Toxicology.................................................................................................................................7 What is Toxicity?..................................................................................................................7 Why is toxicity so important?.............................................................................................8 Drug Toxicity.......................................................................................................................10 Clinical Manifestations..............................................................................................................10 Target organs.............................................................................................................................10 The LIVER (Hepatotoxicity).................................................................................................11 The KIDNEY (Nephrotoxicity)..............................................................................................11 Exposure....................................................................................................................................11 Why is Duration Important?.....................................................................................................13

Adverse Drug Reactions (ADRs)....................................................................................13 General Mechanisms of Toxicity.....................................................................................13 More Specific Mechanisms of Toxicity...........................................................................15 Non-Covalent Interactions.......................................................................................................15 Lipid Peroxidation..................................................................................................................15 Reactive Oxygen Species (ROS)........................................................................................15 Depletion of Glutathione.......................................................................................................16 Modification of Sulfhydryl Groups.......................................................................................16 Covalent Interactions................................................................................................................17

The Dose-Response Relationship..................................................................................18 Measuring Toxicity.............................................................................................................19 Testing for toxicity..............................................................................................................19 Screening for Toxicity..........................................................................................................21 In vitro tests...............................................................................................................................21 In vivo tests................................................................................................................................23 Assessing Toxic Potential........................................................................................................23

Predicting Toxicity..............................................................................................................24 Predicting Toxicity using Computational Methods................................................................24 Pharmacophores and Toxicophores...................................................................................25

References................................................................................................................................29

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Safety Pharmacology

Safety Pharmacology is a rapidly developing discipline that employs the basic principles of pharmacology in a regulatory-driven process to generate data to inform risk/benefit assessment. The aim of Safety Pharmacology is to characterise the pharmacodynamics / pharmacokinetic (PK/PD) relationship of a drug's adverse effects using evolving methodology. Unlike toxicology, Safety Pharmacology includes a regulatory requirement to predict the risk of rare lethal events. This gives Safety Pharmacology its unique character. The key issues for Safety Pharmacology are detection of an adverse effect liability, projection of the data into safety margin calculation and finally clinical safety monitoring.

What is Safety Pharmacology? Safety Pharmacology sets out to predict whether a drug, if administered to human (or animal) populations, is likely to be found unsafe, and its professional mandate is to prevent such an occurrence.

Prior to 1990, pharmaceutical companies conducted toxicological testing of lead compounds as part of preclinical drug discovery. However, over the decades, it has become increasingly clear that drugs may progress as far as phase 3 clinical trials (i.e. the intended patient population) before rare and potentially lethal adverse effects become apparent. The vigilant post-marketing surveillance (PMS) efforts by regulatory authorities necessary to confirm the existence of a rare adverse event occur after approval for human use. Regulatory authorities use tools such as drug experience reports, medical literature (clinical trial data) and multiple agency data sources and spontaneous reporting system (SRS) to monitor adverse drug effect patterns potentially indicative of a public health concern. The SRS receives adverse drug reaction reports derived from health care providers and hospitals. When an adverse effect is very rare, it may require millions of prescriptions before an awareness of its existence emerges. There are numerous examples of this in the literature (for example, Kemp, 1992); one of the best is terfenadine.

In the mid-1990s the antihistamine, terfenadine (Seldane, Marion Merrell Dow), was withdrawn following a growing awareness that the drug could evoke the potentially life-threatening cardiac syndrome, torsades de pointes (TdP), in otherwise healthy patients (Monahan et al., 1990; June and Nasr, 1997). Prior to this, the general perception was that only cardiac/cardiovascular compounds were considered to 3

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possess such a tendency. The problem here was that terfenadine, a noncardiovascular drug, had low efficacy to induce TdP making it so rare an event that it required several million prescriptions before its liability became suspected. The other important consideration here is that the indication for which terfenadine was used (hay fever) is itself far from life threatening. Therefore, risk (death) clearly outweighs benefit (the amelioration of a ‘runny nose'; Rosen, 1996).

This example was of great importance to what we now call Safety Pharmacology (a discipline that did not exist at the time). This is because predicting terfenadine's TdP risk was not possible by the conventional preclinical toxicity testing methods conducted at the time.

See later sections on adverse drug reactions and toxicity testing for more details.

Preclinical toxicology testing, as an approach involved determining the high-dose adverse event profile of a compound given at chronic, toxic doses, but would not have detected a rare lethal event liability at therapeutic dosage. Indeed, screening for TdP risk in animals or in phase 1 and 2 clinical investigations was not recognized as relevant or necessary in the late 1980s and early 1990s. The magnitude of the effect of terfenadine on QT interval is small, and peak effects may exhibit a delayed onset (Ollerstam et al., 2007) and so the effect is hard to detect even if one is looking. This problem could have been avoided if, instead of routine toxicology, a programme of specific high throughput screening (HTS) for TdP liability had been utilized in early drug discovery at the time, but consideration of biomarkers for rare adverse event liability was not part of the toxicology agenda in the early 1990s.

Rationale Regulatory authorities give approval for drug use in humans. Therefore, convincing the regulators that a drug is safe and efficacious is a key part of the drug discovery/development process. Thus, it is important to consider who the regulators are and what they want to know. The structure of a Safety Pharmacology program (see diagram below) is to determine the potential undesirable pharmacodynamic effects of a drug on the central nervous, cardiovascular and respiratory systems, as well as to implement supplementary tests to evaluate other organ systems (Pugsley, 2004; Bass et al., 2004b). Thus it is primarily designed to take account of regulatory requirements; scientific issues are secondary. Follow-up studies may be triggered 4

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if there is a need to characterize specific adverse effects found in initial Safety Pharmacology studies. Although follow-up may appear more scientifically driven than the core programme, the design of follow-up studies is nevertheless based on what is perceived by the pharmaceutical company to be the data required by the regulators. This gives a rather special flavour to Safety Pharmacology—it serves the needs of regulatory authorities primarily, and scientific proof is a secondary issue.

An overview of the multidisciplinary integration required to evaluate the safety profile of a new chemical entity (NCE) in Safety Pharmacology. Consideration is required of the physicochemical and pharmacological nature of the compound, along with toxicological and associated ADME and pharmacokinetic findings.

When there are a large number of drugs that have precise and known relative liabilities for producing common and frequent minor adverse effects it is a simple matter to validate preclinical models using the human template of responses to positive and negative controls. The challenge in Safety Pharmacology is dealing with rare events of a life threatening nature, especially for drugs aimed at treating nonlife-threatening diseases.

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Below is a summary of the main challenges to effective Safety Pharmacology Programs: •

Preclinical safety pharmacology models require better validation

•

Validation requires a quantitative and accurate human template of liabilities of positive and negative controls with which to compare model data sets

•

Validation is not possible for models screening for liabilities that are rare or imprecise with current drugs in humans

•

Validation is also not possible for methods for evaluating human-specific biologics (that are antigenic in animals)

•

It must be understood that interpretation of surrogate biomarker data sets is unavoidably subjective

•

Preclinical safety testing in a non-validated setting must therefore be regarded as non-scientific whereby yes/no judgments will remain subjective in the absence of true validation of the models available

•

Scientific validation of safety testing methods remains the goal, however, elusive this may seem

•

Scientific validation requires blinded randomized testing of drugs known to have and known to not have a liability for the specific adverse effect in humans

•

A rank order of liable drugs in humans (‘gold standard') is the best template

•

It must be acknowledged that a gold standard does not exist for most adverse effect liabilities. This poses a problem

•

In the absence of validation it is better to live with false positives than risk the chance of false negatives.

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Toxicology As already highlighted above, in addition to the pharmacological effect(s) a drug substance may elicit, all drugs have the potential to cause toxicity. In addition to ensuring a new drug compound is efficacious, it is also important to ensure that it does not display significant toxicity. Indeed, in the case of terfenadine, the identification of toxicity is a significant challenge.

What is Toxicity? There are many definitions!

“The degree of strength of a poison” “The ability of a compound to damage cells” “The degree to which a substance (a toxin or poison) can harm humans or animals”

Unlike pharmacological effects, the onset of which is usually relatively rapid, toxic effects can surface after months or even years of drug treatment. Because of this, many toxicities are identified after the drug has been launched and is in widespread use.

The study of toxins can be traced back to the work of Paracelsus (1493-1541), widely accredited as the founder of what we know today as toxicology. He is famous for saying:

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“Poison is in everything and nothing is without poison. The dosage makes it either a poison or a remedy.”

Ultimately, the revelation from this work was that there is no such thing as a truly “safe” drug. Paracelsus was the first to relate the toxicity of a drug to its dosage so was the pioneer of what we know today as the dose-response relationship.

Why is toxicity so important? The toxicity (safety) of drugs in widespread therapeutic use is obviously of major concern. Furthermore, approximately 10% of accident and emergency workload is attributed to toxicity as a result of drug overdosing (often accidental).

To put the scale drug use into perspective, the average person in England had 18.7 prescriptions in 2013 (according to a recent news article on the BBC in December 2014). If you consider the approximate population of England in 2013 was 53.5 million, this equates to over 1 billion prescriptions being made each year. In 2013 alone, the cost to the NHS was in excess of £15 billion.

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Given the widespread use of prescription and over the counter medications, the safety of these drugs is a major concern. Furthermore, many patients are taking multiple medicines simultaneously. In these cases, it is not just the toxicity of each medication that must be assessed, but also how these drugs interact with each other and what effects this may have on efficacy and toxicity.

It is well known (thanks to Paracelsus and his predecessors) that all drugs have the potential to be toxic and all drugs have reported side effects of some kind. In addition to overdose situations, susceptible patients may experience dose-related toxicity even during therapeutic dosing.

With this is mind, there is often a balance between therapeutic efficacy and benefit to the patient and the possible toxicity a drug may elicit.

Of course, the perfect drug (A below), displays perfect efficacy with zero toxicity. However, in reality (B), there is usually a trade-off between drug efficacy and toxicity. A)

B) 100 90 80 70 60 50 40 30 20 10 0

100 90 80 70 60 50 40 30 20 10 0 Efficacy

Toxicity

Efficacy

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Toxicity

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Drug Toxicity The side effects associated with the use of particular drug are referred to commonly as adverse effects or adverse drug reactions (ADRs). These terms incorporate any effect that is not a beneficial therapeutic effect. A particular drug can cause one (or multiple) adverse effects. These effects can themselves be brought about by a single (or multiple) mechanism(s). We will outline some of the major mechanisms of toxicity later.

Clinical Manifestations

Toxic effects are diverse in nature and can include changes in:      

Biochemistry Growth Morphology Development Physiology Lifespan

Patients may present with these at the clinic or these factors may be investigated during clinical trials. Clinical manifestations of toxicity can appear rapidly (within minutes of dosing) or after many years of treatment. The latter makes identifying certain toxicities very difficult since they can only become evident after long-term dosing extending beyond the time frame assessed during clinical trials. The “Clinical Trials” study pack will go into more detail about clinical trial stages and design.

Target organs

When a drug is toxic, the organ it affects is described as the target organ. ADRs are widespread and can affect many different body tissues and system. However, toxicity to the liver and kidney are commonly observed.

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The LIVER (Hepatotoxicity)

The liver is a metabolic powerhouse, designed to convert potentially toxic substances into safer (more soluble) forms for rapid excretion. Unfortunately, in some cases, reactive metabolites can be formed which are more toxic than the parent drug. Hepatocytes are therefore exposed to high concentrations of these reactive metabolites making toxicity to the liver a commonly encountered ADR. NOTE: If it is found that a reactive metabolite is formed and this leads to toxicity, it is often possible to block certain metabolic pathways by replacing the responsible functional group(s) with atoms such as fluorine. However, this may have a knock-on effect on drug efficacy…

The KIDNEY (Nephrotoxicity)

Two major functions of the kidney are to remove waste products from the blood and to reabsorb water. However, drugs (and their polar metabolites) therefore concentrate in renal tubular fluid as water is reabsorbed, meaning the renal tubules are potentially exposed to high concentrations of toxins.

Exposure

The exposure of a patient to a drug is a key element of toxicity and is dependent upon the route of administration. As can be seen from the diagram below, oral administration renders a drug susceptible to first pass metabolism and possible metabolic activation. 11

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Exposure to drugs can be via a single dose or by multiple doses over differing durations. Typically, medications are prescribed as multiple doses over a period of a few days to many months/years. Exposure is categorised as follows:

Exposure Class Acute Subacute

Duration of exposure 3 months

Dose Single dose Repeated doses Repeate...