[Place and role of safety pharmacology in drug development].
Safety pharmacology is a key regulatory step for drug development and approval. Prior to phase I, the effects of a drug candidate should be evaluated and characterized on vital functions (cardiovascular, respiratory and central nervous system) according to good laboratory practice standards. For cardiovascular evaluation, effects on blood pressure and electrocardiogram should be explored with a particular emphasis on ventricular repolarization prolongation, a major risk factor for life-threatening arrhythmias, like "torsades de pointe". Global behaviour, motor activity, reflexes and body temperature should be evaluated in animals. A dedicated study is necessary for respiratory function evaluation. All of these studies should be conducted after single administration of the compound administered by the anticipated clinical route. Dependence potential and abuse liability should be characterized for innovative drugs and/or drugs acting on the central nervous system. Evidence for adverse effects at discovery stage with high throughput systems is becoming a key step of decision-making process for pharmaceutical industry. Therefore, determination of the safety margin, risk/benefit ratio analysis and investigation of adverse effects are major decisional elements for providing safety reassurance to patients. Safety of patients will also be improved through modelling methodologies allowing a safer transposition of experimental pharmacology results to clinical pharmacology.
Guillon
J-M
JM
Département Deposition Safety & Animal Research, Groupe de Pharmacologie, Sanofi-Aventis, 3 digue d'Alfortville, 94140 Alfortville, France. Jean-michel.guillon@sanofi-aventis.com
D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D005602:France; D006801:Humans; D007880:Legislation, Drug; D010601:Pharmacology, Clinical / Q000592:standards*; D012137:Respiratory System / Q000187:drug effects; D012449:Safety