The successes and limitations of preclinical studies in predicting the pharmacodynamics and safety of cell-surface-targeted biological agents in patients.

British Journal of Pharmacology
Andrew G Polson, Reina N Fuji

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.

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Citations

Nov 23, 2012·Expert Opinion on Drug Safety·Hugo M VargasMichael J Engwall
Mar 16, 2013·Annals of the New York Academy of Sciences·Myrtle DavisPaul B Watkins
Dec 18, 2014·MAbs·Leon A G J M van AertsChristian K Schneider
Jan 24, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ágota PetőIldikó Bácskay
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Sep 20, 2017·Expert Review of Proteomics·Hyunsoo KimYoungsoo Kim
Dec 7, 2020·Journal of Experimental Orthopaedics·Elisha JohnstonDavid Rabago
Jan 3, 2021·Cell and Tissue Banking·Bagher LarijaniBabak Arjmand
Jul 3, 2021·International Journal of Molecular Sciences·Olga SergeevaTimofei Zatsepin
Jul 3, 2021·International Journal of Molecular Sciences·Vincent KuekLaurence C Cheung
Aug 28, 2021·Animals : an Open Access Journal From MDPI·Wentao XieDietmar Zechner

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