Integration of safety pharmacology endpoints into toxicology studies

Abstract

In the ILSI Human Toxicity Program, human toxicity was identified with 94% in studies of 1 month or less duration. Safety pharmacology studies and 1 month toxicity studies are prerequisites of INDs. These studies contributed in 69% to the predictivity of human toxicity. Correlating data from pharmacology and toxicology data will therefore enhance the predictivity of human toxicity. The ILSI Human Toxicity Program also showed that non-rodent toxicology studies were more predictive of human toxicity than rodents. Consequently, the usage of non-rodents, especially dogs, produces data more relevant to the safety of humans. Integration of data from safety pharmacology and pharmacological endpoints from integrated toxicology studies, which cover a wide dose range, allow data interpretation also concerning chronic effects. Differences in relation to chronic exposure and species specific pharmacodynamic effects can be taken into consideration. In vivo data in pharmacology are taken from a larger number of species. Usually, pharmacokinetic data and histopathology are often lacking in pharmacology (e.g. guinea pig). Studies in a smaller number of species, which are incorporating pharmacology, pharmacodynamic and toxicology, allow also crossinterpretation with data from clinical chemistry, haematology and histopathology. Endpoints relating to behaviour (functional observation battery/FOB) and cardiovascular toxicity can be integrated into regulatory toxicology. Technical progress in non-invasive methodology and refined measurements for pharmacological parameters and standardization of study design allow the incorporation into regulatory toxicity studies today. The limitations of conducting pharmacological measurements in regulatory toxicology studies are acknowledged. Safety pharmacology studies should complement toxicity studies in terms of choice of species and dose regimen. Ethical usage of animals, especially dogs or monkeys, can only be justified in the future, when more clinically relevant data can be gained from fewer in vivo studies. Multidisciplinary co-operation between pharmacology, pharmacokinetics and toxicology will lead to refinements and reduction of in-vivo studies when functional parameters are integrated into regulatory studies.

Principles of Safety Pharmacology

“…Beyond routine CNS Safety Pharmacology evaluations, some models are developed to characterize specific neurological adverse effects with the use of EEG monitoring by telemetry ( Durmuller et al ., 2007 ). A trend to integrate some components of the Safety Pharmacology evaluations such as respiratory, CNS and ECG study end points into toxicology studies is currently noted ( Luft and Bode, 2002 ). Development of non‐invasive methodologies such as ECG monitoring (along with respiration, temperature and animal activity) using jacketed external telemetry systems has significantly contributed to this emerging practise ( Morton et al ., 2003 ).…”

Evaluation of a general toxicity study incorporating phototoxicity assessments in Sprague-Dawley rats

“…Additionally, the Guidance for Industry Photosafety Testing (2003) published by the Food and Drug Administration (FDA) specifies, "assessments of photoirritation may be incorporated into ongoing general toxicity studies in some circumstances." Toxicology studies incorporating genotoxicity (Hamada et al, 2001) and pharmacological safety (Luft and Bode, 2002) assessments have already been reported. These reports indicate that combining multiple studies shortens the research and development period and reduces the number of experiments and animals required.…”

Status of Safety Pharmacology and Present Guidelines

“…These early organ function assessments were normally disjointed and disconnected from the results of the toxicology program. Attempts to add organ function endpoints to toxicology protocols were frustrated by the fact that data were collected without regard to the physiological status of the subjects and/or pharmacokinetic parameters (Lufy & Bode 2002;Morgan et al 1994). …”