DOSE-EFFECT RELATIONSHIP.ppt

DOSE-EFFECT RELATIONSHIP The intensity and duration of a drug’s effects are a function of the drug dose and drug concentration at the effect site Frank M. Balis, M.D. January 25, 2007 Monitoring Dose-Effect Level Molecular (e.g, enzyme inhibition) Cellular (in vitro tissue culture, blood cells) Tissue or organ (in vitro or in vivo) Organism Endpoint used to measure effect may be different at each level Overall effect = sum of multiple drug effects and physiological response to drug effects Dose-Effect Endpoints Erythropoietin and Anemia Drug-Receptor Interactions Dose-Effect Relationship Graded Dose-Effect Curve Log Dose-Effect Curve Lidocaine Graded Dose-Effect Theophylline Dose-Effect Metformin Dose-Response Dose-Effect Parameters Comparing Dose-Effect Curves Thiopurine Cytotoxicity Receptor-Mediated Effects Drug Interactions Graded Dose-Effect Analysis Identify the therapeutic dose/concentration Define site of drug action (receptor) Classify effect produced by drug-receptor interaction (agonist, antagonist) Compare the relative potency and efficacy of drugs that produce the same effect Assess mechanism of drug interactions Quantal Dose-Effect Distribution Cumulative Dose-Effect Curve Cumulative Dose-Effect Study Therapeutic and Toxic Effects Doxorubicin Cardiotoxicity Lidocaine Quantal Dose-Effect Antihypertensive Dose-Effect Antihypertensive Drugs Dose Intensity in Breast Cancer Doxorubicin Dose in Osteosarcoma Relating Dose to Effect In Vivo Effect Compartment (PK/PD Model) Concentration and Effect vs. Time Hysteresis and Proteresis Loops Role of Dose-Effect Studies Drug development Site of action Selection of dose and schedule Potency, efficacy and safety Drug interactions Patient management Therapeutic drug monitoring Risk-benefit (therapeutic indices) Endpoints to Monitor Drug Effect Thiopurine Metabolic Activation Therapeutic Indices Relative Dose Intensity Oral Mercaptopurine Pharmacodynamic Models Fixed effect model Linear model Log-linear model Emax mod