title: The successes and limitations of preclinical studies in predicting the pharmacodynamics and safety of cell-surface-targeted biological agents in patients.
abstract: To improve drug development outcomes, it is important to review when preclinical pharmacodynamic and safety models have successfully predicted human responses and when they have not. In a recent issue of the BJP, Bugelski and Martin examined the concordance between preclinical and human data for biopharmaceuticals targeted to cell-surface proteins. The cases are interesting and several trends emerge. The pharmacodynamics of biopharmaceuticals in non-human primates is largely predictive; the use of surrogates in rodents may be similarly predictive, allowing for more conservative use of non-human primates. While overall concordance of preclinical toxicology data and clinical safety was poor, this is largely a reflection of the immunomodulatory biology of the majority of the biopharmaceuticals evaluated. The examples show that adverse effects in animals that were the result of direct and/or exaggerated pharmacology were modelled well, but that specific infections or other indirect outcomes of immunomodulation, along with cytokine-related events, were not modelled well in preclinical studies.
authors.affiliation: Genentech Research and Early Development, South San Francisco, CA, USA. polson@gene.com
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Polson
authors.forename: Reina N
authors.initials: RN
authors.lastname: Fuji
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000633:toxicity*; D006801:Humans; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology* / Q000633:toxicity*
chemical_list: D000911:Antibodies, Monoclonal; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins