Inclusion of Safety Pharmacology Endpoints in Repeat-Dose Toxicity Studies

Abstract

Whereas pharmacological responses tend to be fairly rapid in onset and are therefore detectable after a single dose, some diminish on repeated dosing, and others increase in magnitude and therefore can be missed or underestimated in single-dose safety pharmacology studies. Safety pharmacology 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 and 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 function. This is entirely achievable if the safety pharmacology 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.

Physical Properties and Effect in a Battery of Safety Pharmacology Models for Three Structurally Distinct Enteric Polymers Employed as Spray-Dried Dispersion Carriers

“…Pre-clinical models have been established to screen NCEs for effects on GI function including gastric absorption, secretion, and emptying, gastrointestinal motility, as well as nausea and emesis liabilities (Al-Saffar et al, 2015 ). Drug-induced effects on GI function can be assessed as endpoints integrated into toxicology studies (Redfern, 2015 ) or, as in the present study, in stand-alone safety pharmacology studies. In the present investigation, studies were performed using a barium sulfate test meal to assess effects on gastric emptying and GI transit time.…”

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.…”

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.…”