title: 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.
authors.affiliation: Institute for Pathology and Toxicology at Byk Gulden, Altana Pharma, Hamburg, Germany. Joerg.Luft@byk.de
authors.forename: Jörg
authors.initials: J
authors.lastname: Luft
authors.forename: Gerd
authors.initials: G
authors.lastname: Bode
mesh_terms: D000818:Animals; D023381:Endpoint Determination / Q000379:methods* / Q000592:standards; D017408:Guidelines as Topic; D006801:Humans; D010601:Pharmacology, Clinical / Q000379:methods / Q000592:standards*; D011786:Quality Control; D013045:Species Specificity; D013678:Technology, Pharmaceutical / Q000592:standards*; D018675:Toxicity Tests / Q000379:methods / Q000592:standards; D014116:Toxicology / Q000379:methods / Q000592:standards*