Overview of Safety Pharmacology

Sonia Goineau1, Martine Lemaire1, Guillaume Froget1

1 Porsolt S.A.S, Le Genest‐Saint‐Isle
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 10.1
DOI:  10.1002/0471141755.ph1001s63
Online Posting Date:  December, 2013
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Abstract

Safety pharmacology entails the assessment of the potential risks of novel pharmaceuticals for human use. As detailed in the ICH S7A guidelines, safety pharmacology for drug discovery involves a core battery of studies on three vital systems: central nervous (CNS), cardiovascular (CV), and respiratory. Primary CNS studies are aimed at defining compound effects on general behavior, locomotion, neuromuscular coordination, seizure threshold, and vigilance. The primary CV test battery includes an evaluation of proarrhythmic risk using in vitro tests (hERG channel and Purkinje fiber assays) and in vivo measurements in conscious animals via telemetry. Comprehensive cardiac risk assessment also includes full hemodynamic evaluation in a large, anesthetized animal. Basic respiratory function can be examined in conscious animals using whole‐body plethysmography. This allows for an assessment of whether the sensitivity to respiratory‐depressant effects can be enhanced by exposure to increased CO2. Other safety pharmacology topics detailed in this unit are the timing of such studies, ethical and animal welfare issues, and statistical evaluation. Curr. Protoc. Pharmacol. 63:10.1.1‐10.1.8. © 2013 by John Wiley & Sons, Inc.

Keywords: safety pharmacology; risk assessment; ICH S7A guidelines; central nervous system; cardiovascular system; respiratory system

     
 
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Table of Contents

  • Introduction
  • Terminology
  • Safety Pharmacology Versus Toxicology
  • Comparison of Japanese and ICH Guidelines
  • CNS Safety Pharmacology
  • Cardiovascular Safety Pharmacology
  • Respiratory Safety Pharmacology
  • Timing of Safety Pharmacology Studies and Good Laboratory Practice
  • Ethical and Animal Welfare Issues
  • Statistical Evaluation
  • Conclusions
  • Literature Cited
  • Tables
     
 
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Materials

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Literature Cited

  Dürmüller, N., Guillaume, P., Lacroix, P., Porsolt, R.D., and Moser, P. 2007. The use of the dog electroencephalogram (EEG) in safety pharmacology to evaluate proconvulsant risk. J. Pharmacol. Toxicol. Methods 56:234-238.
  Fossa, A.A. 1994. Inaugural conference on general pharmacology/safety pharmacology. Drug Dev. Res. 32:205.
  Gengo, P.J., Pettit, H.O., O'Neill, S.J., Su, Y.F., McNutt, R., and Chang, K.J. 2003. DPI‐3290 [(+)‐3‐((α‐R)‐α‐((2S,5R)‐4‐Allyl‐2,5‐dimethyl‐1‐piperazinyl)‐3‐hydroxybenzyl)‐N‐(3‐fluorophenyl)‐N‐methylbenzamide]. I. A mixed opioid agonist with potent antinociceptive activity and limited effects on respiratory function. J. Pharmacol. Exp. Ther. 307:1221-1226.
  Goineau, S., Rompion, S., Guillaume, P., and Picard, S. 2010. Ventilatory function assessment in safety pharmacology: Optimization of rodent studies using normocapnic or hypercapnic conditions. Toxicol. Appl. Pharmacol. 247:191-197.
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  Japanese Ministry of Health and Welfare. 1995. Japanese Guidelines for Nonclinical Studies of Drugs Manual 1995: Guidelines for Toxicity Studies of Drugs: Guidelines for General Pharmacology Studies: Guidelines for Nonclinical Pharmacokinetic Studies. Pharmaceutical Affairs Bureau, Japanese Ministry of Health and Welfare. Yakugi Nippo, Japan.
  Kuryshev, Y.A., Ficker, E., Wang, L., Hawryluk, P., Dennis, A.T., Wible, B.A., Brown, A.M., Kang, J., Chen, X.L., Sawamura, K., Reynolds, W., and Rampe, D. 2005. Pentamidine‐induced long QT syndrome and block of hERG trafficking. J. Pharmacol. Exp. Ther. 312:316-323.
  Lacroix, P. and Provost, D. 2000. Basic safety pharmacology: The cardiovascular system. Thérapie 55:63-69.
  Moser, P., Wolinsky, T., Duxon, M., and Porsolt, R.D. 2011. How good are current approaches to nonclinical evaluation of abuse and dependence? J. Pharmacol. Exp. Ther. 336:588-595.
  Murphy, D.J. 2002. Assessment of respiratory function in safety pharmacology. Fund. Clin. Pharmacol. 16:183-196.
  Murphy, D.J. 2005. Comprehensive non‐clinical respiratory evaluation of promising new drugs. Toxicol. Appl. Pharmacol. 207:414-424.
  Murphy, D.J., Renninger, J.P., and Schramek, D. 2010. Respiratory inductive plethysmography as a method for measuring ventilatory parameters in conscious, non‐restrained dogs. J. Pharmacol. Toxicol. Methods 62:47-53.
  Picard, S., Goineau, S., Guillaume, P., Henry, J., Hanouz, J.L., and Rouet, R. 2011. Supplemental studies for cardiovascular risk assessment in safety pharmacology: A critical overview. Cardiovasc. Toxicol. 11:285-307.
  Porsolt, R.D., Picard, S., and Lacroix, P. 2005. International safety pharmacology guidelines (ICH S7A and S7B): Where do we go from here? Drug Dev. Res. 64:83-89.
  Porsolt, R.D., Castagné, V., Dürmüller, N., and Moser, P. 2007. CNS safety pharmacology. In Nonclinical Drug Safety Assessment: Practical Considerations for Successful Registration (W.K. Sietsema and R. Schwen, eds.) pp. 141-162. FDA News, Washington, D.C.
  Pugsley, M.K., Authier, S., and Curtis, M.J. 2008. Principles of safety pharmacology. Br. J. Pharmacol. 154:1382-1399.
  Redfern, W.S., Ewart, L.C., Lainée, P., Pinches, M., Robinson, S., and Valentin, J.‐P. 2013. Functional assessments in repeat‐dose toxicity studies: The art of the possible. Toxicol. Res. 2:209-234.
  Sullivan, A.T. and Kinter, L.B. 1995. Status of safety pharmacology in the pharmaceutical industry—1995. Drug Dev. Res. 35:166-172.
  U.S. Food and Drug Administration. 2001. S7A safety pharmacology studies for human pharmaceuticals (ICH Guidance for Industry). U.S. Food and Drug Administration, Rockville, Md.
  U.S. Food and Drug Administration. 2005. S7B nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals (ICH Guidance for Industry). U.S. Food and Drug Administration, Rockville, Md.
  Van den Hoogen, R.H. and Colpaert, F.C. 1986. Respiratory effects of morphine in awake unrestrained rats. J. Pharmacol. Exp. Ther. 237:252-259.
Internet Resources
  http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM074959.pdf
  The FDA's S7A safety guidelines for pharmacology studies of human pharmaceuticals.
  http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM074963.pdf
  The FDA's S7B safety guidelines for pharmacology studies of human pharmaceuticals.
  http://www.ich.org/products/guidelines.html
  Contains links to both the ICH S7A (Safety Pharmacology Studies for Human Pharmaceuticals) and S7B (The Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) By Human Pharmaceuticals) safety guidelines.
  http://www.oecd.org
  The OECD Web site contains comprehensive information about GLPs.
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