L9: Safety Pharmacology/Toxicology in Drug Development

What is safety pharmacology? Safety pharmacology is the detection of the risk of adverse drug reactions. Always need to consider RISK and BENEFIT what is primary pharmacodynamic stud- detection of potential adverse reactions ies by the the intended molecular target what is secondary pharmacodynamic studies Detection of potential adverse reactions mediated by off target actions Terfenadine ADRs we didn't expect which was not identified by toxicology investigations give an example of a drug that led to the and thousands of patients had taken the emergence of safety pharmacology. drug before this adverse drug reaction was identified. Which gave rise to safety pharmacology, which work to make sure only safe drugs are given to humans. when is a substance a drug? a substance is a drug is the benefit exceeds risk, at overdose risk exceeds benefit. Key factors to consider: NOEL, NOAEL, severity of the disease, severity of the adverse drug reactions. Determining the therapeutic window What is the no observable effect level (NOEL)? other factors include: - Exposure length of the administration of the drug months/years - If the ADR is lethal any exposure may be unsafe, if the drug is administered only briefly the exposure is low highest dose at which no therapeutic effect is detected what is no observable adverse effect lev- highest dose at which no ADR is detectel (NOAEL) ed what is attrition ? attrition is when a drug in development fails and is abandoned 1/3 what is frontloading ? target validation is intergrated with safety assessment at every stage of development. certain chemical structures as known to be associated with particular adverse drug reaction - toxic pharmacophore what is a class effect if the drug class has benefit only when the toxic pharmacophore is present, this is called a CLASS EFFECT What is a drug-drug interaction (DDI)? when one drug alters the rate or extent of absorption, distribution, metabolism or excretion, or effect of another drug this may increase adverse drug reactions of either drug what is a core battery a core battery refers to a set of standard tests or measurements that are routinely used to assess the safety and efficacy of new drugs before they are approved for human use. The core battery is designed to provide a basic level of information about a drug's effects on the body, and to identify any potential safety concerns. These tests are conducted to ensure that the drug does not have harmful effects on major body systems: Assessments involved in core battery 1) Cardiovascular assessment 2) CNS assessment 3) Respiratory assessment used to evaluate the potential cardiovascardiovascular assessment of core bat- cular risks associated with the drug.: tery ECG, blood pressure monitoring, patch 2/3 clamp, haemodynamics (study of how blood moves through our body) - permanently implants a small devise into animals cardiovascular assessment in conscious - allows free roaming animals telemetered animals - battery life for 2 years - reliable signal for BP and LVP, stable consistent ECG The CNS includes the brain and spinal cord. conducted in animal models to evaluate the potential effects of a drug on the CNS: CNS assessment in core battery most CNS ADRs impact 'quality of life' rather than 'risk to life' but some are directly or indirectly life-threatening. Approaches of studying ADRs in nervous system: - in vitro electrophysiology - imaging what influences ADRs risk PK properties 3/3