Abstract
Pharmacokinetics is essentially the study of “how a substance gets into the body and what happens to it in the body.” Similarly, toxicokinetics deals with what the body does with a drug or other substance when given a relatively high dose relative to the therapeutic dose. Toxicokinetic studies are generally carried out at much higher doses than those used in pharmacokinetic studies, and this dose information is critical for predicting the safety of substances. The primary objective of toxicokinetics is to describe the systemic exposure achieved in animals and its relationship to dose level and the time course of the toxicity study. The ratio of drug exposure in animals at the no observed adverse effect level (NOAEL) and in humans at the expected therapeutic dose is one of the precautionary principles to determine the risk benefit profile of pharmaceuticals.
This is a preview of subscription content, log in via an institution.
References and Further Reading
BVA/FRAME/RSPCA/UFAW Working Group of Refinement (1993) Removal of blood from laboratory mammals and birds. Lab Anim 27:1–22
Cayen MN (1995) Considerations in the design of toxicokinetic programs. Toxicol Pathol 23(2):148–157
Diehl K-H, Hull R, Morton D, Pfister R, Rabemampianina Y, Smith D, Vidal J-M, van de Vorstenbosch C (2001) A good practice guide to the administration of substances and removal of blood, including routes and volumes. J Appl Toxicol 21:15–23
EMEA CHMP SWP Reflection Paper on PPARs (peroxisome proliferator activated receptors); Doc Ref: EMEA/341972/2006 (2006)
FDA Guidance for Industry S6 Preclinical Safety Evaluation of Biotechnology- Derived Pharmaceuticals (1997)
FDA Guidance for Industry Safety Testing of Drug Metabolites (2008)
ICH Focus on Microsampling (2017) Note for guidance on toxicokinetics: the assessment of systemic exposure – focus on microsampling (CHMP/ICH/320985/2016); adopted by CPMP December 2017
ICH Guidance on Toxicokinetics (1994) ICH topic S3 A; toxicokinetics: a guidance for assessing systemic exposure in toxicology studies (CPMP/ICH/384/95); approval by CPMP November 1994
ICH Topic S1C(R2) (2008) Dose selection for carcinogenicity of pharmaceuticals (EMEA/CPMP/ICH/383/1995); approval by CPMP April 2008
Lacy SA, Hitchcock MJM, Lee WAL, Tellier P, Cundy KC (1998) Effect of oral probenecid coadministration on the chronic toxicity and pharmacokinetics of intravenous cidofovir in cynomolgus monkeys. Toxicol Sci 44:97–106
Lee MS, Kerns EH (1999) LC/MS applications in drug development. Mass Spectrom Rev 18:187–279
Pai SM, Fettner SH, Hajian G, Cayen MN, Batra VK (1996) Characterization of AUCs from sparsely sampled populations in toxicology studies. Pharm Res 13(9):1283–1290
Ramirez T, Beken S, Chlebus M, Ellis G, Griesinger C, de Jonghe S, Manou I, Mehling A, Reisinger K, Rossi LH, van Benthem J, van der Laan JW, Weissenhorn R, Sauer UG (2015) Knowledge sharing to facilitate regulatory decision-making in regard to alternatives to animal testing: report of an EPAA workshop. Regul Toxicol Pharmacol 73:210–226
Welling PG (1995) Differences between pharmacokinetics and toxicokinetics. Toxicol Pathol 23:143–147
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this entry
Cite this entry
Sombogaard, F. (2019). Toxicokinetics and Safety Ratios. In: Hock, F., Gralinski, M. (eds) Drug Discovery and Evaluation: Methods in Clinical Pharmacology. Springer, Cham. https://doi.org/10.1007/978-3-319-56637-5_21-1
Download citation
DOI: https://doi.org/10.1007/978-3-319-56637-5_21-1
Received:
Accepted:
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-56637-5
Online ISBN: 978-3-319-56637-5
eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences