Abstract
Non-clinical studies are conducted in drug development to demonstrate safety and efficacy for drug candidates prior to their use in clinical studies and throughout drug development. Toxicokinetic studies are conducted in the non-clinical phase to determine systemic exposure to a drug as a function of its dose. The data are also used to support the design of subsequent studies in different species, routes of administration, formulations, and dose levels, and to relate any toxicological findings to potential clinical safety and efficacy in humans. For regulated toxicokinetic studies, the study samples are analyzed by validated bioanalytical methods that should provide reliable and robust quantitative results. In this chapter we discuss how to determine toxicokinetic parameters in non-clinical studies and how to validate the bioanalytical methods that are used to analyze non-clinical samples, and we briefly discuss immunogenicity and the impact it can have on the toxicokinetic profile.
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References and Further Reading
Andrade EL, Bento AF, Cavalli J, Oliveira SK, Schwanke RC, Siqueira JM, Freitas CS, Marcon R, Calixto JB (2016) Non-clinical studies in the process of new drug development - part II: good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies. Braz J Med Biol Res 49(12):e5646. https://doi.org/10.1590/1414-431X20165646
Avila AM, Bebenek I, Bonzo JA, Bourcier T, Davis Bruno KL, Carlson DB, Dubinion J, Elayan I, Harrouk W, Lee SL, Mendrick DL, Merrill JC, Peretz J, Place E, Saulnier M, Wange RL, Yao J, Zhao D, Brown PC (2020) An FDA/CDER perspective on non-clinical testing strategies: classical toxicology approaches and new approach methodologies (NAMs). Regul Toxicol Pharmacol 114:104662. https://doi.org/10.1016/j.yrtph.2020.104662
Butler LD, Guzzie-Peck P, Hartke J, Bogdanffy MS, Will Y, Diaz D, Mortimer-Cassen E, Derzi M, Greene N, DeGeorge JJ (2017) Current non-clinical testing paradigms in support of safe clinical trials: an IQ consortium DruSafe perspective. Regul Toxicol Pharmacol 87 Suppl 3:S1–S15. https://doi.org/10.1016/j.yrtph.2017.05.009
Ducret A, Ackaert C, Bessa J, Bunce A, Hickling T, Jawa V et al (2022) Assay format diversity in preclinical immunogenicity risk assessment: towards a possible harmonization on antigenicity assays. MAbs 14(1):1993522. https://doi.org/10.1080/19420862.2021.1993522
European Medicines Agency, Committee for Medicinal Products for Human Use, (2011) Guideline on bioanalytical method validation, London, UK
Gibaldi M, Perrier D (1982) Pharmacokinetics, Second edn. Marcel Dekker, Inc., New York
Guidance for Industry. Safety testing of drug metabolites guidance for Industry. March 2020. Pharmacology/Toxicology Revision 2. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER)
International Council for Harmonisation of technical requirements for pharmaceuticals for human use. ICH S3A, 1994. Toxicokinetics: the assessment of systemic exposure in toxicity studies.
International Council for Harmonisation of technical requirements for pharmaceuticals for human use. ICH S6(R1), 2011. Preclinical safety evaluation of biotechnology-derived pharmaceuticals.
International Council for Harmonisation of technical requirements for pharmaceuticals for human use. ICH M10, 2022. Bioanalytical method validation and study sample analysis.
International Council for Harmonisation of technical requirements for pharmaceuticals for human use. ICH M3(R2), 2009. Non-clinical safety studies for the conduct of human clinical trials and marketing.
Kropshofer H, Singer T (2006) Overview of cell-based tools for preclinical assessment of immunogenicity of biotherapeutics. J Immunotoxicol 3(3):131–136. https://doi.org/10.1080/15476910600845625
Lauren A, Goodman J, Blaes J, Cook J, Cowan KJ, Dahlbäck M, Grudzinka-Goebel J, McManus D, Nelson R, Pihl S, Timmerman P (2021) A strategic approach to non-clinical immunogenicity assessment: a recommendation from the European Bioanalysis Forum. Bioanalysis 13(7):537–549. https://doi.org/10.4155/bio-2021-0028
Lynch CM, Hart BW, Grewal IS (2009) Practical considerations for non-clinical safety evaluation of therapeutic monoclonal antibodies. MAbs 1(1):2–11. https://doi.org/10.4161/mabs.1.1.7377
Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, Lilly P, Sanders J, Sipes G, Bracken W, Dorato M, Van Deun K, Smith P, Berger B, Heller A (2000) Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 32(1):56–67. https://doi.org/10.1006/rtph.2000.1399. PMID: 11029269
Shankar G, Pendley C, Stein K (2007) A risk-based bioanalytical strategy for the assessment of antibody immune responses against biological drugs. Nat Biotech 25(5):555–561. https://doi.org/10.1038/nbt1303
Stevenson L, Zinnack K, Donley J, Beebe L, Amaravadi L (2011) Paradigm of combination biologics: analytical challenges related to pharmacokinetic assays and interpretation of pharmacokinetic and immunogenicity results. Bioanalysis 3(5):487–498. https://doi.org/10.4155/bio.10.214
Thway T, Magana I, Bautista A, Jawa V, Gu W, Ma M (2013) Impact of anti-drug antibodies in preclinical pharmacokinetic assessment. AAPS J 15(3):856–863. https://doi.org/10.1208/s12248-013-9484-4
US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (2018) Guidance for industry: bioanalytical method validation. US FDA, Rockville
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Scheel Fjording, M., Hays, A., Kousba, A. (2023). Bioanalytical Assays: Toxicokinetic. In: Hock, F.J., Gralinski, M.R., Pugsley, M.K. (eds) Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays. Springer, Cham. https://doi.org/10.1007/978-3-030-73317-9_100-1
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DOI: https://doi.org/10.1007/978-3-030-73317-9_100-1
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