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

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.

Safety Pharmacology Investigations on the Nervous System: An Industry Survey

“…In a previous industry survey conducted in 2012 by the SPS, 34% of participants had experience with inclusion of FOB in toxicology studies (Authier et al, 2013), possibly indicating increasing experience with the study designs and/or increasing development of biotherapeutic agents over the last three years. When conducted by experienced groups, FOB/Irwin Test assessments were shown to be robust to identify CNS drug effects with known CNS-active agents (Porsolt et al, 2002;Moscardo et al, 2007;Redfern et al, 2005;Ewart et al, 2013), justifying the addition of CNS endpoints in toxicology studies, useful in a 3R"s context (Redfern et al, 2013;Redfern, 2015). A wide range of group sizes was reported (i.e.…”

Functional Assessments in Nonhuman Primate Toxicology Studies to Support Drug Development

“…An obvious benefit of incorporating functional end points into toxicology studies is that it allows assessment of repeat dosing and long-term exposure on vital organ function, in contrast to stand-alone safety pharmacology studies, which typically assess the effects of single-dose administration [13,25]. After multiple doses, functional effects with delayed onset may occur (e.g., following accumulation of the test article in a particular organ or inhibition of ion channel trafficking) or tolerance of initial effects may develop (e.g., due to receptor internalization).…”

“…Many of the toxicities are functional in nature and/or in origin. Whereas pharmacological responses tend to have fairly rapid onset and are therefore detectable after a single dose, some diminish upon repeated dosing; others increase in magnitude and therefore can be missed or underestimated in single-dose safety pharmacology studies [13].…”

“…In addition to these general toxicology studies, specialized repeat-dose toxicity studies are also required and include rodent carcinogenicity, reproductive toxicology, and juvenile toxicity studies [3,[7][8][9][10][11][12][13].…”

Reducing Drug Attrition: Safety Pharmacology

“…A few examples are listed. With the availability of jackets for collecting cardiovascular and respiratory data in dogs and monkeys, safety pharmacology endpoints can be captured in toxicology studies [22,23]. Human stem cell-derived cardiomyocytes are being investigated as a new model for safety pharmacology studies [24].…”