Safety Pharmacology Overview

Safety pharmacology Detection of potential adverse drug reactions at therapeutic dose Primary Pharmacodynamic Studies Detection of potential ADRs mediated by intended molecular target Secondary Pharmacodynamic Studies Detection of potential ADRs mediated by 'off target' actions Dosage Determines if a substance is a poison or remedy Therapeutic window Dose/concentration range where drug benefits outweigh ADRs NOEL Highest dose with no therapeutic effect NOAEL Highest dose with no ADR detected Therapeutic window determination Based on NOEL, NOAEL, disease severity, and ADR severity Maximum 'safe' concentration (MSC) Relative concept set by risk:benefit analysis Exposure in drug administration Extent of patient exposure to a drug Type A ADRs Dose-dependent, predictable ADRs from drug properties Type B ADRs Idiosyncratic, unpredictable ADRs not always dose-related Type C ADRs Long-term adaptive changes with some drug classes Type D ADRs Delayed effects like carcinogenicity or teratogenicity Type E ADRs Rebound effects after discontinuation of therapy Population dose response relationships Relationship between drug dose and therapeutic, adverse, lethal effects ED50 Effective dose for 50% of individuals AD50 Adverse dose for 50% of individuals LD50 Lethal dose for 50% of individuals 1/4 Dose response relationship Relationship between drug dose and response Detriment in drug exposure Balance between ADR detriment and drug benefit Goal of therapeutic drug Provide benefit outweighing any detriment Role of Safety Pharmacology (SP) Mitigate risks of drug-related detriment Supratherapeutic Effect Interaction causing heightened adverse drug reactions Secondary ADR Off-target actions not on primary molecular target Non-Specific Effects Adverse reactions with unknown mechanisms Active Metabolites Metabolites causing adverse drug reactions Torsades de Pointes Rare ventricular arrhythmia leading to cardiac arrest Safety Pharmacology Field focusing on adverse drug reaction prevention Regulatory Toxicology Studies assessing drug toxicity for regulatory approval Attrition Abandonment of a drug in development due to failure Frontloading Integrating safety assessment early in drug development Toxic Pharmacophore Chemical structures linked to specific adverse reactions Class Effect Benefit seen only when toxic pharmacophore is present Drug-Drug Interactions (DDI) Alteration of one drug's effects by another drug Cytochrome P450 Enzyme system involved in drug metabolism 2/4 Safety Assessment Evaluating drug safety to prevent adverse reactions GLP Good Laboratory Practice for quality assurance Type A Predictable adverse effect type Primary endpoints Key measurements in a study Dosing regimen Scheduled drug administration plan Cardinal exposure parameter Key measure of drug exposure Trend tests Statistical analysis for identifying patterns Study design Framework for conducting research Margins Safety factor in risk assessment Cmax Maximum drug concentration in blood AUC Area under the drug concentration curve Sex of animals Gender distribution in research subjects Core Battery Essential tests in safety pharmacology QT prolongation Heart rhythm disorder biomarker FIH First-in-Human studies SP assessment Safety Pharmacology evaluation Neuronal cultures In vitro nerve cell studies Functional Observation Battery Assessment of animal behavior in tests PK properties Pharmacokinetic characteristics of a drug Second generation antihistamines Antihistamines with low brain penetration Terfenadine Drug with sedation and other issues Yanai et al. Authors of a pharmacology study Predicted brain penetration Used to reject compounds early Blood-brain barrier Barrier that drugs must cross for CNS effects 3/4 logBB+ drugs Expect CNS ADRs with good brain penetration logBB- drugs Minimal CNS ADRs due to poor brain penetration FOB/Irwin Tests for locomotor activity, seizures, abuse liability Convulsion Involuntary muscle contractions Seizure Abnormal brain activity, may not involve convulsions EEG Measures brain activity, used for seizure assessment Drug discrimination Assesses if compound effects mimic known drugs Physical dependence Assessment of withdrawal syndrome after chronic use Respiratory assessment Evaluates effects on lung function and gas exchange GI safety assessment Evaluates effects on gastrointestinal system Integrated risk assessment Determines drug safety based on various factors 4/4