Safety pharmacology investigations on the nervous system: An industry survey

Abstract

The Safety Pharmacology Society (SPS) conducted an industry survey in 2015 to identify industry practices as they relate to central, peripheral and autonomic nervous system ('CNS') drug safety testing. One hundred fifty-eight (158) participants from Asia (16%), Europe (20%) and North America (56%) responded to the survey. 52% of participants were from pharmaceutical companies (>1000 employees). Oncology (67%) and neurology/psychiatry (66%) were the most frequent target indications pursued by companies followed by inflammation (48%), cardiovascular (43%), metabolic (39%), infectious (37%), orphan (32%) and respiratory (29%) diseases. Seizures (67% of participants), gait abnormalities (67%), tremors (65%), emesis (56%), sedation (52%) and salivation (47%) were the most commonly encountered CNS issues in pre-clinical drug development while headache (65%), emesis/nausea (60%), fatigue (51%) and dizziness (49%) were the most frequent issues encountered in Phase I clinical trials. 54% of respondents reported that a standard battery of tests applied to screen drug candidates was the approach most commonly used to address non-clinical CNS safety testing. A minority (14% of all participants) reported using electroencephalography (EEG) screening prior to animal inclusion on toxicology studies. The most frequent group size was n=8 for functional observation battery (FOB), polysomnography and seizure liability studies. FOB evaluations were conducted in a dedicated room (78%) by blinded personnel (66%) with control for circadian cycle (55%) effects (e.g., dosing at a standardized time; balancing time of day across treatment groups). The rat was reported as the most common species used for seizure liability, nerve conduction and drug-abuse liability testing.

Screening for Neurotoxicity with Microelectrode Array

“…To date, the benchmark assay for in vitro detection of seizure liability has been the hippocampal brain slice assay (Authier et al, 2016;Easter et al, 2007;Wahab et al, 2010). This technique, however, is limited by throughput and the need for sophisticated instrumentation and expertise.…”

“…Although some of these assays can detect morphological, physiological, and electrophysiological alterations, they are not designed to detect deleterious changes to the normal function of neural networks as a whole (Bradley, Luithardt, Metea, & Strock, 2018;McConnell, McClain, Ross, LeFew, & Shafer, 2012;Novellino et al, 2011;Prado, Ross, DeWeerth, & LaPlaca, 2005). Until recently, the most commonly used in vitro assay for the detection of compounds that disrupt neural network activity and organization is the hippocampal brain slice assay (Authier et al, 2016;Bradley et al, 2018;Easter, Sharp, Valentin, & Pollard, 2007;Wahab, Albus, Gabriel, & Heinemann, 2010). This has been the benchmark assay for the functional assessment of neural network disruptions, however, it is a low throughput assay that requires significant expertise and complex electrophysiological recording devices.…”

In vitro Models for Seizure-Liability Testing Using Induced Pluripotent Stem Cells

“…Central nervous system (CNS) toxicity testing of any new pharmaceutical is a vital procedure and legal requirement for safety pharmacology studies ( ICH, 2000 ). A drug-induced seizure is an example of a potentially fatal ADR and is the most commonly encountered CNS-related issue during the drug development process ( Authier et al, 2016 ). Pre-clinical seizure-liability (PSL) testing is essential to identify such ADRs; however, these tests usually occur late in the drug development process ( Figure 1 ; Easter et al, 2007 ).…”

A Framework Proposal to Follow‐Up on Preclinical Convulsive Signals of a New Molecular Entity in First‐in‐Human Studies Using Electroencephalographic Monitoring

“…Drug‐induced convulsions may present as a serious, potentially life‐threatening adverse drug reaction and are one of the most frequent causes of central nervous system related injury or death in human clinical trials . For dose‐escalating FiH trials—particularly for nononcology indications typically conducted in healthy volunteers with the requirement to minimize safety risk—the uncertainty in interspecies translatability of convulsive risk has resulted in a generalized approach that limits dose escalation to a 10‐fold safety margin between the estimated plasma levels in dose‐escalation studies in humans and the plasma level associated with the NOEL for convulsions in animal toxicity studies . According to a cross‐industry survey conducted together with the “Innovation and Quality” Consortium–DruSafe Leadership Group (https://iqconsortium.org/; unpublished data), 88% of DruSafe members apply the 10‐fold safety margin for FiH studies in healthy volunteers, either because of a perceived expectation from regulatory reviewers or sponsors’ tendencies to apply a conservative approach for safety reasons.…”