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Global Approach in Safety Testing pp 119–158Cite as

Toxicokinetics: A Guidance for Assessing Systemic Exposure in Toxicology Studies, Where Are We Now; An S3A/S3B Update (1995–2011)

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Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 5))

Abstract

The ICH S3A and S3B guidances written in 1995 have been critically examined by one author whom helped write the original guidance and the other who has had to put them into practice. The objectives of the guidances were to clarify across the three regions when, what and how drug levels in pivotal safety studies should be measured using GLP-validated methods and how the results could be used to reduce the number of exploratory animal pharmacokinetic studies and reduce their emphasis. Although it has formed a good basic framework to move forward, subsequent guidances have been required. These have included the metabolites in safety testing (MIST) providing further information on which metabolites to measure and when disproportionate human levels not qualified in animals need to be further tested and bioanalytically validated. New advances in sampling techniques, composite and auto-sampling, microsampling with plasma separation, dried blood spot analysis (DBS) and kinetic population approaches of the data to enable serial concomitant sampling are discussed. Other topics of uncertainty which are discussed include when to measure tissue distribution (ICH S3B), should exposure measurement be included in in vitro studies (mutagenicity, hERG, cytotoxicity, etc.), should protein binding be measured at NOAEL and safety margins expressed as total or free unbound levels and when is Cmax more appropriate than AUC. It is suggested that toxicokinetic–toxicodynamic relationships should be investigated more frequently where possible using established biomarkers.

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Authors and Affiliations

  1. Department of Pharmacology, Kings College Guys Campus London, Proximagen Neuroscience, London, UK

    Bruce Campbell

  2. RMI-Pharmacokinetics, Carlsbad, CA, USA

    Bob Ings

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  1. Bruce Campbell
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  2. Bob Ings
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Correspondence to Bruce Campbell .

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Editors and Affiliations

  1. , Section on Pharmacology, Toxicology, and, Medicines Evaluation Board, Graadt van Roggenweg 500, Utrecht, 3531 AH, Netherlands

    Jan Willem van der Laan

  2. , Drug Safety Testing, Merck Research Laboratories, Sumneytown Pike 770, West Point, 19486, Pennsylvania, USA

    Joseph J. DeGeorge

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© 2013 American Association of Pharmaceutical Scientists

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Campbell, B., Ings, B. (2013). Toxicokinetics: A Guidance for Assessing Systemic Exposure in Toxicology Studies, Where Are We Now; An S3A/S3B Update (1995–2011). In: van der Laan, J., DeGeorge, J. (eds) Global Approach in Safety Testing. AAPS Advances in the Pharmaceutical Sciences Series, vol 5. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5950-7_7

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