L8: Safety pharmacology and toxicology part 2 Flashcards
regulatory requirements- ICH guidance?
ICH - International Conference on Harmonisation
(of technical requirements for registration of pharmaceuticals for human use)
Regulatory authorities of Europe, Japan and the United States
Pharmaceutical companies follows guidance when seeking a license (e.g., from FDA in the US) for human use
ICH S7A guidance covers 3 stated objectives
To identify potential ADRs in nonhuman settings (e.g., hypotension in a rat)
= Hazard Identification
To evaluate potential ADR by toxicology assessment (nonclinical) and safety assessment (nonclinical and clinical)
= Risk Assessment
To investigate the mechanism of the adverse effects observed and/or suspected
= Risk Management and Mitigation (minimisation).
regulatory studies?
the laws require certain studies to be undertaken (‘regulatory’ studies)
Regulatory toxicology
Acute in vivo general toxicology
In vivo genotoxicity and mutagenicity
Chronic in vivo general toxicology
Developmental and reproductive toxicology
Carcinogenicity
Regulatory Safety Pharmacology studies (see later)
attritition
‘Attrition’ is when a drug in development ‘fails’ and is abandoned. in the past, attrition was mainly due to lack of benefit. Poor pharmacokinetics for example. or molecular target was not infact useful. Now main reason for drug failiure is ADRs.
front loading
In drug development, target validation is a key part of the discovery phase, where researchers confirm that acting on a specific biological target (like a protein or receptor) is likely to produce the desired therapeutic effect. This phase also includes proof of concept studies to test whether the proposed mechanism works.
Importantly, target validation is integrated with safety assessment at every stage of development. While discovery focuses on therapeutic effectiveness, safety assessment looks at possible adverse effects—particularly:
On-target (augmented) adverse drug reactions (ADRs): These occur when a drug hits its intended target but causes harmful effects, especially at high (supratherapeutic) doses, or when the target is also present in unintended tissues.
During compound safety assessment, the focus shifts to the drug itself and its potential to cause:
Off-target ADRs: Unintended effects due to interaction with other molecules not meant to be targeted.
Metabolite-related ADRs: Harmful effects caused by the drug’s breakdown products.
To manage these risks early, high-throughput screening (HTS) and follow-up studies are used to identify red flags before the drug moves too far through development. However, non-specific effects (e.g., immune reactions or unexpected biological interactions) are much harder to detect—especially when they are human-specific. This is a significant challenge for biologics, such as monoclonal antibodies, which may behave differently in animal models compared to humans.
general considerations for safety assessment
Some chemical structures are known to be associated with particular ADRs - ‘toxic pharmacophore’
If the drug class has benefit only when the toxic pharmacophore is present, this is called a ‘class effect’
Drug – Drug interactions (DDI)
DDI: when one drug alters the rate or extent of absorption, distribution, metabolism or excretion, or effect of another drug
This may increase ADRs of either drug
e.g. cimetidine reduces the clearance of theophylline
because theophylline is metabolised by cytochrome p450, and cimetidine inhibits p450
safety pharmacology vs toxicology
historical distinction
increasingly ADR assessment is managed by people in Safety Assessment
toxicology is increasingly becoming very limited in scope
The distinction between Safety Pharmacology and Toxicology is quite arbitrary, and ‘territorial’. Increasingly all these functions will be Safety…
Primary adverse effect type predicted: safety pharm- type A, general toxicology- Types C-E
primary endpoints: safety pharm- functional responses/ effects, general toxicology- cross clinical signs; histopathology
dosing regimen: safety pharm- single dose (usually), general toxicology- chronic, repeat-dose
cardinal exposure parameter: safety pharm- Cmax, PKPD modelling, general toxicology- AUC
basis for risk assessment: safety pharmacology- margins, general toxicology, NOAEL
overall objectives of safety pharmacology
To build Confidence in Safety (CIS)” by moving all attrition into the nonclinical phase of drug discovery
To provide the data and guidance to help decisions to be made about the starting dose and range for Phase I (human) studies
ICH S7A: Regulatory agencies require, as a minimum, nonclinical safety data for the 3 systems deemed critical for life:
These studies, required by laws, are the ‘core battery’
To provide follow-up studies for mechanistic understanding of ADRs during clinical trials
key aspects of ICH S7A guidance
Core battery and any supplemental follow-up must be conducted prior to first human exposure (FIH)
Core battery should ordinarily be conducted to GLP
Follow-up supplemental studies should be conducted to GLP ‘to the greatest extent feasible’
For in vivo studies, the clinical route of administration should be used where feasible
The dose-relationship and time course of the ADR should be investigated
Doses /concentrations should include and exceed the intended therapeutic range
Human-specific metabolites should also be evaluated
FIH
Preclinical safety and discovery are designed to provide data to seek approval for FIH
Experiment selection must be justified (necessary and sufficient)
Guidance on follow up studies is somewhat subjective
Selection should be based on what makes scientific sense
When documents are prepared, the company must judge what is necessary and what is sufficient for FIH approval
This involves a cost/benefit calculation
Some S7A requirements may be disregarded for certain types of drugs or intended use
Trivial novelty, e.g., new salt having similar PK and PD to an established drug will not normally require full SP assessment
No need for full SP assessment for locally applied agents (e.g., dermal) with low systemic absorption or exposure
SP is almost irrelevant for agents for end-stage cancer, unless drug has a novel mechanisms of action
For highly selective biologics, it may be sufficient to evaluate ADR as part of toxicology and/or pharmacodynamic studies
For biologics that are a novel therapeutic class, or are not highly selective, SP studies may be required
