Safety pharmacology--current and emerging concepts

Abstract

Safety pharmacology (SP) is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials. SP studies are described in the International Conference on Harmonisation (ICH) S7A and S7B guidelines. The core battery and supplemental SP studies evaluate effects of a new chemical entity (NCE) at both anticipated therapeutic and supra-therapeutic exposures on major organ systems, including cardiovascular, central nervous, respiratory, renal and gastrointestinal. This review outlines the current practices and emerging concepts in SP studies including frontloading, parallel assessment of core battery studies, use of non-standard species, biomarkers, and combining toxicology and SP assessments. Integration of the newer approaches to routine SP studies may significantly enhance the scope of SP by refining and providing mechanistic insight to potential adverse effects associated with test compounds.

Keywords: ADR; AKI; ALP; ALT; AP; AST; Adverse Drug Reaction; BP; BUN; CLU; CNS; CVS; Cardiovascular; Cardiovascular System; Central Nervous System; Central nervous system; ECG; EEG; EMA; Electrocardiogram; European Medicines Agency; FDA; FOB; Food and Drug Administration; Functional Observation Battery; GFR; GGT; GI; GST; Gastrointestinal; Glomerular Filtration Rate; HR; ICH; International Conference on Harmonisation; KIM-1; LDH; N-acetyl-β-d-glucosaminidase; NCE; NGAL; NMR; Neutrophil gelatinase-associated lipocalin; New Chemical Entity; Nuclear Magnetic Resonance; PBPK; PEB; RPA-1; Respiratory; Risk; SP; Safety Pharmacology; Safety pharmacology; TFF3; VQM; Ventilation (V)/perfusion (Q) mismatch (M); action potential; acute kidney injury; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; blood pressure; blood urea nitrogen; clusterin; electroencephalography; glutathione S transferase; hERG; hESC; heart rate; human Ether-a-go-go related gene; human embryonic stem cells; kidney injury molecule-1; lactate dehydrogenase; miR; microRNA; photoelectric beam interruption technique; physiologically based pharmacokinetics; renal papillary antigen-1; trefoil factor 3; β-NAG; γ-glutamyl transferase.