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Nonclinical Safety Evaluation of Drugs
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Thomas M. Monticello, Jeanine L. Bussiere
The ICH S7A (2000) and ICH S7B (2005) guidance documents provide the general principles and recommendations for safety pharmacology studies. Safety pharmacology studies are defined as those studies that investigate the potential undesirable effects on physiologic functions in relation to the exposure in the clinical therapeutic range and above. The core battery of safety pharmacology studies consists of the assessment of effects on the cardiovascular system, the CNS, and the respiratory system. In accordance with ICH S7A and S7B, the core battery of studies should be completed prior to FIH clinical trials.
Safety Pharmacology
Published in David Woolley, Adam Woolley, Practical Toxicology, 2017
Historically, both these areas of experiment have been referred to as general pharmacology. Safety pharmacology is a refinement of secondary pharmacodynamics in that it looks typically at a defined set of organs (as detailed in the core battery) and tends to ask more general questions of test systems (although some are very specific, as we shall see). ICH guideline S7A (2000) defines safety pharmacology as “those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above.” The overall intention is to identify effects of the kind that have led to the withdrawal of successful drugs from the market, sometimes after many years of consumer exposure. One of the challenges to this intention is that some of the more serious reactions to drugs are idiosyncratic and thus will not be identified by any of the nonclinical studies–including safety pharmacology. Safety pharmacology, therefore, is not a catchall discipline infallibly weeding out dangerous drugs; however, when used critically, it can be a useful tool in the risk assessment process that leads to the authorization to market a new drug. These studies may also highlight effects that may be expected in cases of human overdose.
Identification and Use of Biomarkers in Preclinical Toxicologic Safety Assessment
Published in Anthony P. DeCaprio, Toxicologic Biomarkers, 2006
Donna M. Dambach, Jean-Charles Gautier
In vivo assessment of safety pharmacology using physiological and clinical pathology biomarkers is an established standard of preclinical safety assessment that is a part of International Conference for Harmonization (ICH) guidelines (9). Addition of in vitro biomarker platforms for particular safety pharmacology organ assessment during the lead optimization phase provides an earlier indication of potential safety issues (10,11). This type of strategy not only provides a mechanism to evaluate structurally distinct chemical series for concurrent efficacy and safety optimization, but also buys time for follow-up studies to verify any suspect findings and determine their relevance (11–13).
Neurotoxic and cardiotoxic effects of N-methyl-1-(naphthalen-2-yl)propan-2-amine (methamnetamine) and 1-phenyl-2-pyrrolidinylpentane (prolintane)
Published in Drug and Chemical Toxicology, 2023
Sohee Jeong, Kyung Sik Yoon, Jin-Moo Lee, Eun Sung Jo, Dojung Kim, Sun Ok Choi
Amphetamine has been regulated by all 183 states since 1971 by the United Nations Convention on Psychotropic Substances (UNODC 2007). Due to these regulations, illegal drug users have started to use NPS (Ministry of Health, Labor and Welfare 2015). Methamphetamine, one of the amphetamine substitute drugs, is a compound with a similar structure to 1-(benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB) and, thus, prohibited in Japan. Animal experiments conducted using positive control drugs or central stimulants, such as amphetamine, significantly contributed to developing drug regulations. Prolintane is also a CNS stimulant with similar structural and pharmacological properties to d-amphetamine (Hollister and Gillespie 1970). The side-effects of d-amphetamine include insomnia, nervousness, irritability, and dizziness (Martinez-mir et al. 1997). The overuse of prolintane can cause hallucination, substance use disorder, and schizophrenia and, eventually, death (Kyle and Daley 2007). However, the data on the toxicity and carcinogenicity of many NPSs are minimal. Particularly, there is a lack of research exploring the CNS and cardiovascular system (ICH 1997). Safety abbreviations have regulated the medicines related to NPSs through guidelines established by the International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use. Safety pharmacology tests can be used to screen any issues with human organs, including the nervous, cardiovascular, and respiratory systems.
18th Annual Meeting of the Safety Pharmacology Society: drug safety assessment on gastrointestinal system functions
Published in Expert Opinion on Drug Safety, 2020
Icilio Cavero, Henry H. Holzgrefe
Safety Pharmacology (SP) is a drug development discipline regulated by the S7A and S7B guidelines [1] which are official documents of the International Conference on Harmonization (ICH). The ICH was a joint initiative of the European Union, Japan and the USA to which other countries have adhered. Its mission is to prepare a mutually recognised and applied body of regulations on the standards of undoubted safety, excellent quality and satisfactorily proved efficacy that new medicines for human use have to possess. The stated objective of the ICH S7A guideline is ‘to help protect clinical trial participants and patients receiving marketed products from potential adverse effects of pharmaceuticals while avoiding unnecessary use of animals and other resources. The guideline provides a definition, general principles, and recommendations for safety pharmacology studies’ [1]. Hence, the chief objective of SP is to ensure that drugs for first-in-human (FIH) trials are free of life-threatening liabilities on any physiological system, and primarily on the cardiovascular, respiratory and central nervous organ functions.
The 2-year rodent bioassay in drug and chemical carcinogenesis testing: Sensitivity, according to the framework of carcinogenic action
Published in Toxicology Mechanisms and Methods, 2020
Jose D. Suarez-Torres, Fausto A. Jimenez-Orozco, Carlos E. Ciangherotti
In this respect, recall that toxicity tests can be considered as screening testing (Suarez-Torres et al. 2020). The framework mentioned above has been applied in both toxicology and safety pharmacology testing by authoritative authors and institutions (Valentin et al. 2009; Pugsley et al. 2011; EFSA 2011; U.K. COM 2011). As a result, statements on the utility of toxicity tests that disregard their performance can be significantly prone to error. According to the framework mentioned above, the performance of nonclinical tests refers to their ability to distinguish the positives and negatives correctly, all according to what was labeled by the gold standard (Miller et al. 2006; Gordis 2014; Suarez-Torres et al. 2020).