Jump to main content
Jump to site search

Issue 4, 2013
Previous Article Next Article

Functional assessments in repeat-dose toxicity studies: the art of the possible

Author affiliations

Abstract

Clinical and nonclinical safety liabilities remain a major cause of adverse drug reactions, candidate drug attrition, delays during development, labelling restrictions, non-approval, and product withdrawal. Many of the toxicities are functional in nature and/or in origin. Whereas pharmacological responses tend to be fairly rapid in onset, and are therefore detectable after a single dose, some diminish on repeated dosing, whereas others increase in magnitude and therefore can be missed or underestimated in single-dose safety pharmacology studies. Functional measurements can be incorporated into repeat-dose toxicity studies, either routinely or on an ad hoc basis. Drivers for this are both scientific (see above), and regulatory (e.g., ICH S6, S7, S9). There are inherent challenges in achieving this: the availability of suitable technical and scientific expertise in the test facility; unsuitable laboratory conditions; use of simultaneous (as opposed to staggered) dosing; requirement for toxicokinetic sampling; unsuitability of certain techniques (e.g., use of anaesthesia; surgical implantation; food restriction); equipment availability at close proximity; sensitivity of the methods to detect small, clinically relevant, changes. Nonetheless, ‘fit-for-purpose’ data can still be acquired without requiring additional animals. Examples include assessment of behaviour, sensorimotor, visual, and autonomic functions, ambulatory ECG and blood pressure, echocardiography, respiratory, gastrointestinal, renal and hepatic functions. This is entirely achievable if functional measurements are relatively unobtrusive, both with respect to the animals and to the toxicology study itself. Careful pharmacological validation of any methods used, and establishing their detection sensitivity, is vital to ensure the credibility of generated data.

Graphical abstract: Functional assessments in repeat-dose toxicity studies: the art of the possible

Back to tab navigation
Please wait while Download options loads

Publication details

The article was received on 02 Dec 2012, accepted on 11 Mar 2013 and first published on 12 Mar 2013


Article type: Review Article
DOI: 10.1039/C3TX20093K
Citation: Toxicol. Res., 2013,2, 209-234
  •   Request permissions

    Functional assessments in repeat-dose toxicity studies: the art of the possible

    W. S. Redfern, L. C. Ewart, P. Lainée, M. Pinches, S. Robinson and J. Valentin, Toxicol. Res., 2013, 2, 209
    DOI: 10.1039/C3TX20093K

Search articles by author