Safety pharmacology preclinical evaluation

There are two general approaches to the in vivo preclinical evaluation of safety pharmacology. Such evaluation can either be performed as (separate) free-standing studies focused solely on the pharmacologic endpoints of concern or as integral evaluations conducted as on animals that are part of a modified safety assessment study [38,43]. 

The pharmacokinetic evaluation of biopharmaceuticals is generally simplified by the usual metabolism of products to small peptides and to amino acids, and thus classical biotransformation and metabolism studies are rarely necessary. Routine studies to assess mass balance are not useful. However, both single- and multiple-dose toxicokinetic data are essential in safety pharmacology asessments, and these can be complicated by two factors (1) biphasic clearance with a saturable, initial, receptor-dependent clearance phase, which may cause nonlinearity in dose-exposure relationships and doseresponses [14] and (2) antibody production against an antigenic biopharmaceutical that can alter clearance or activity in more chronic repeat-dose safety studies in the preclinical model. 

PURPOSE AND RATIONALE Measurement of cardiac function and morphology is a key part of the preclinical evaluation of experimental medicinal compounds. Blood pressure, heart rate, and electrocardiogram evaluation are part of the core portfolio of safety pharmacology studies carried out in conscious telemetry dogs. If results from the core battery of tests raise concern then supplemental studies are conducted to measure endpoints such as left ventricular pressure, pulmonary arterial pressure, heart rate variability, baroreflex, cardiac output, ventricular contractility and vascular resistance. However, many... 

Topic S6 Note for Preclinical Safety Evaluation of Biotechnology-Derived Products Topic S7A Note for Guidance on Safety Pharmacology Studies for Human Pharmaceuticals... 

Provides the general study design framework for in vitro and in vivo preclinical evaluations of TdP. Spedfically places evaluations addressing risk for repolarization-associated ventricular tachyarrhythmia within the safety pharmacology domain. 

---