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Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays pp 5–16Cite as

Status of Safety Pharmacology and Present Guidelines

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Abstract

Ray Lipicky (Director, LIPICKY, LLC, A Consulting Company; retires from FDA in February 2002) started one of his presentations with the following slide:

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References and Further Reading

  • Ackerman MJ (1998) The long QT syndrome: ion channel diseases of the heart. Mayo Clin Proc 73:250–269

    Article  PubMed  CAS  Google Scholar 

  • Anderson ME, Al-Khatib SM, Roden DM, Califf RM (2002) Cardiac repolarization: current knowledge, critical gaps and new approaches to drug development and patient management. Am Heart J 144:769–781

    PubMed  CAS  Google Scholar 

  • Anon (2008) Guidance for industry diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. U.S. Department of Health and Humans Services, Food and Drug Administration, Center for Drug Evaluation and Research. www.fda.gov/downloads/drugs/GuidanceComplianceRegulatoryInformation/guidances/UCM071627.pdf. Accessed Dec 2008

  • Baldrick P, Bamford DG, Tattersall ML (1998) An assessment of two gastric transport models currently used in safety pharmacology testing. Hum Reprod Toxicol 17:1–7

    Article  CAS  Google Scholar 

  • Bass AS, Williams PD (2003) Status of international regulatory guidelines on safety pharmacology. In: Williams PD, Bass AS (eds) Safety Pharmacology, pp 9–20

    Google Scholar 

  • Bass A, Kinter L, Williams P (2004a) Origins, practices and future on safety pharmacology. J Pharmacol Toxicol Methods 49:145–151

    Article  PubMed  CAS  Google Scholar 

  • Bass AS, Vargas HM, Kinter LB (2004b) Introduction to nonclinical safety pharmacology and the Safety Pharmacology Society. J Pharmacol Toxicol Methods 49:141–144

    Article  PubMed  CAS  Google Scholar 

  • Bass AS, Vargas HM, Valentin J-P, Kinter LB, Hammond T, Wallis R, Siegl PKS, Yamamoto K (2011) Safety pharmacology in 2010 and beyond: survey of significant events of the past 10 years and a roadmap to the immediate-, intermediate- and long-term future in recognition of the tenth anniversary of the Safety Pharmacology Society. J Pharmacol Toxicol Methods. doi:10.1016/j.vascn.2011.05.006

    Google Scholar 

  • Batey AJ, Doe CPA (2003) A method for QT correction based on beat-to-beat analysis of the QT/RR interval relationship in conscious telemetered beagle dogs. J Pharmacol Toxicol Methods 48:1–9

    Google Scholar 

  • Bunting PB, Siegl PKS (1994) Models used to assess cardiovascular function in general pharmacology. Drug Dev Res 32:256–259

    Article  CAS  Google Scholar 

  • Calamari D (2003) Strategic survey of therapeutic drugs in the rivers Po and Lambo in Northern Italy. Environ Sci Technol 37:1241–1248

    Article  CAS  Google Scholar 

  • Cavero I, Crumb W (2005) ICH S7B draft guideline on the non-clinical strategy for testing delayed cardiac repolarisation risk of drugs: a critical analysis. Expert Opin Drug Saf 4:509–530

    Article  PubMed  Google Scholar 

  • Champeroux P, Martel E, Fowler JSL, Maurin A, Sola ML, Jude S, Elamrani F, Weyn AA, Laveissiere A, Lala P, Richard S (2009) Calculation of QT shift in non clinical safety pharmacology studies. J Pharmacol Toxicol Methods 59:73–85

    Article  PubMed  CAS  Google Scholar 

  • Champeroux P, Ouillé A, Martel E, Fowler JSL, Maurin A, Jude S, Lala P, Guennec J-Y, Richard S (2010) Interference of the autonomic nervous system with drug induced QT prolongation: a point to consider in non-clinical safety studies. J Pharmacol Toxicol Methods 61:251–263

    Article  PubMed  CAS  Google Scholar 

  • Chiu PJS (1994) Models used to assess renal function. Drug Dev Res 32:247–255

    Article  CAS  Google Scholar 

  • De Ponti F, Poluzzi E, Montanaro N (2001) Organising evidence on QT prolongation and occurrence of torsades de pointes with non-antiarrhythmic drugs: a call for consensus. Eur J Clin Pharmacol 57:185–209

    Article  PubMed  Google Scholar 

  • Del Rio CL, Kijtawornrat A, Hamlin RL, Billman GE (2010) Beat-to beat changes in QT/RR relationships induced by ischemia on dogs prone to sudden death are modeled by QT-shortening, not lengthening. J Pharmacol Toxicol Methods 62:e45–e46

    Google Scholar 

  • Deurinck M, Traebert M (2008) Body temperature-induced QT shortening in dogs: a case report. J Pharmacol Toxicol Methods 58:159

    Google Scholar 

  • Gad SC (2004) Safety pharmacology in pharmaceutical development and approval. CRC Press, Boca Raton

    Google Scholar 

  • Green MD (1995) An FDA perspective on general pharmacology studies to determine activity and safety. Drug Dev Res 35:158–160

    Article  CAS  Google Scholar 

  • Haggerty GC (1991) Strategy for and experience with neurotoxicity testing of new pharmaceuticals. J Am Coll Toxicol 10:677–687

    Article  Google Scholar 

  • Hammond TG, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Redfern WS, Sullivan AT, Camm AJ (2001) Methods of collecting and evaluating non-clinical cardiac electrophysiology data in pharmaceutical industry: results of an international survey. Cardiovasc Res 49:741–750

    Article  PubMed  CAS  Google Scholar 

  • Haverkamp W, Breithart G, Camm AJ, Janse MJ, Rosen MR, Antzelevitch C, Escande D, Franz M, Malik M, Moss A, Shah R (2000) The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Cardiovasc Res 47:219–233

    Article  PubMed  CAS  Google Scholar 

  • Himmel HM, Hoffmann M (2010) QTc shortening with a new investigational cancer drug: a brief case study. J Pharmacol Toxicol Methods 62:72–81

    Article  PubMed  CAS  Google Scholar 

  • Holbrook M, Malik M, Shah RR, Valentin J-P (2009) Drug induced shortening of the QT/QTc interval: an emerging safety issue warranting further modeling and evaluation in drug research and development? J Pharmacol Toxicol Methods 59:21–28

    Article  PubMed  CAS  Google Scholar 

  • Holzgrefe HH, Cavero I, Gleason CR, Warner WA, Buchanan LV, Gill MW, Burkett DE, Durham SK (2007a) Novel probalistic method for precisely correcting the QT interval for heart rate in telemetered dogs and cynomolgus monkeys. J Pharmacol Toxicol Methods 55:159–175

    Article  PubMed  CAS  Google Scholar 

  • Holzgrefe HH, Cavero I, Buchanan LV, Gill MW, Durham SK (2007b) Application of a probalistic method for the determination of drug-induced QT prolongation in telemetered cynomolgus monkeys: effects of moxifloxacin. J Pharmacol Toxicol Methods 55:244–254

    Article  Google Scholar 

  • Hondeghem LM, Carlsson L, Duker G (2001) Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic. Circulation 103:2004–2013

    Article  PubMed  CAS  Google Scholar 

  • Huggett DB, Khan IA, Foran CM, Schlenk D (2003) Determination of beta-adrenergic receptor blocking pharmaceuticals in United States wastewater effluent. Environ Pollut 121:199–205

    Article  PubMed  CAS  Google Scholar 

  • Igarashi T, Nakane S, Kitagawa T (1995) Predictability of clinical adverse reactions of drugs by general pharmacology studies. J Toxicol Sci 20:77–92

    Article  PubMed  CAS  Google Scholar 

  • Jackson CO (1970) Doctor Massengill’s elixir. In: Jackson CO (ed) Food and drug legislation in the new deal. Princeton University Press, Princeton, pp 151–174

    Google Scholar 

  • Japanese Ministry of Health and Welfare (1995) Japanese guidelines for nonclinical studies of drugs manual 1995. Yakuji Nippo, Tokyo

    Google Scholar 

  • Kinter LB (2003) Safety pharmacology of the renal and gastro-intestinal systems. In: Williams PD, Bass AS (eds) Safety pharmacology: a practical guide. TherImmune Research, Gaithersburg, pp 99–116

    Google Scholar 

  • Kinter LB, Dixon LW (1995) Safety pharmacology program for pharmaceuticals. Drug Dev Res 35:179–182

    Article  CAS  Google Scholar 

  • Kinter LB, Johnson DK (1999) Remote monitoring of experimental endpoints in animals using radiotelemetry and bioimpedance technologies. In: Hendriksen CFM, Morton DB (eds) Proceedings of the international conference on humane endpoints in animal experiments for biomedical research. The Royal Society of Medicine Press, London, pp 58–65

    Google Scholar 

  • Kinter LB, Johnson DK (2003) Safety pharmacology of the cardiovascular system. In: Williams PD, Bass AS (eds) Safety pharmacology: a practical guide. TherImmune Research, Gaithersburg, pp 67–98

    Google Scholar 

  • Kinter LB, Valentin JP (2002) Safety pharmacology and risk assessment. Fundam Clin Pharmacol 16:175–182

    Article  PubMed  CAS  Google Scholar 

  • Kinter LB, Gossett KA, Kerns WD (1994) Status of safety pharmacology in the pharmaceutical industry—1993. Drug Dev Res 32:208–216

    Article  CAS  Google Scholar 

  • Kinter LB, Murphy DJ, Mann WA, Leonard TB, Morgan DG (1997) Major organ systems toxicology: an integrated approach to pharmacodynamic safety assessment studies in animals. In: Williams PD, Hottendorf GH (Series eds), Sipes IG, McQueen CA, Gandolfi AJ (Vol eds) Comprehensive toxicology: toxicology testing and evaluation, vol 2. Elsevier, New York, pp 155–168

    Google Scholar 

  • Kopin DW, Furlong ET, Meyer MT, Thurman EM, Zaugg SD, Barber LB, Buxton HT (2002) Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams 1999–2000: a national reconnaissance. Environ Sci Technol 36(6):1202–1211

    Article  Google Scholar 

  • Kramer K, Kinter LB (2003) Evaluation and application of radiotelemetry in small laboratory animals. Physiol Genomics 13:197–205

    PubMed  Google Scholar 

  • Kramer K, Mills PA, Kinter LB, Brockway BP (1998) History of laboratory telemetry and the state of the art of fully implanted radiotelemetry for monitoring laboratory animals. Lab Anim 27:40–46

    Google Scholar 

  • Kurata M, Kanai K, Mizuguchi K, Yoshida M, Nakamura K, Furuga Y, Kinoue A, Totsuka K, Igarashi S (1997) Trends in safety pharmacology in the US and Europe. J Toxicol Sci 22:237–248

    Google Scholar 

  • Lacroix P, Provost D (2000) Basic safety pharmacology: the cardiovascular system. Therapie 55:63–69

    PubMed  CAS  Google Scholar 

  • Leber P (2002) Regulatory issues. In: Davis KL, Charney D, Coyle JZ, Nemeroff C (eds) Neuropsychpharmacology: the fifth generation of progress. American College of Neuropsychopharmacology, Brentwood, pp 485–494

    Google Scholar 

  • Lipicky R To the heart of the matter: cardiac safety of non-cardiac drugs. http://spo.escardio.org/eslides/view.aspx?eevtid=40&fp=201

  • Lu HR, van Bergen P, Vlaminckx E, Rohrbacher J, Hermans A, van Ammel K, Towrd R, Pugley MK, Gallacher DJ (2008a) Drug-induced QT shortening and fibrillation: through or not thorough QT, that is the question? Heart 94:e1

    Google Scholar 

  • Lu HR, Vlaminckx E, Hermans AN, Rohrbacher J, van Ammel K, Toward R, Pugsley M, Gallacher DJ (2008b) Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs points to gaps in the ICHS7B guidelines. Br J Pharmacol 154:1427–1438

    Article  PubMed  CAS  Google Scholar 

  • Lufy J, Bode G (2002) Integration of safety pharmacology endpoints into toxicology studies. Fundam Clin Pharmacol 16:91–103

    Article  Google Scholar 

  • Lumley CE (1994) General pharmacology, the international regulatory environment, and harmonization guidelines. Drug Dev Res 32:223–232

    Article  Google Scholar 

  • Malik M, Camm AJ (2001) Evaluation of drug-induced QT interval prolongation. Implications for drug approval and labelling. Drug Saf 24:323–351

    Article  PubMed  CAS  Google Scholar 

  • Marshall E (2001a) Volunteer’s death prompts review. Science 292:2226–2227

    Article  PubMed  CAS  Google Scholar 

  • Marshall E (2001b) Procedures faulted in fatal asthma trial. Science 293:405–406

    Article  PubMed  CAS  Google Scholar 

  • Mattsson JL, Spencer PJ, Albee RR (1996) A performance standard for chemical and functional observation battery examinations of rats. J Am Coll Toxicol 15:239–254

    Article  Google Scholar 

  • Miller HI (2000) Gene therapy’s trials and tribulations. The Scientist 14:16–18

    Google Scholar 

  • Mojaverian P (1996) Evaluation of gastrointestinal pH and gastric residence time via the Heidelberg radiotelemetry capsule: pharmacological application. Drug Dev Res 38:73–85

    Article  CAS  Google Scholar 

  • Morgan DG, Kelvin AS, Kinter LB, Fish CJ, Kerns WD, Rhodes G (1994) The application of toxicokinetic data to dosage selection in toxicology studies. Toxicol Pathol 22:112–123

    Article  PubMed  CAS  Google Scholar 

  • Mortin LI, Horvath CJ, Wygand MS (1997) Safety pharmacology screening: practical problems in drug development. Int J Toxicol 16:41–65

    Article  CAS  Google Scholar 

  • Moser VC (1991) Application of a neurobehavioral screening battery. J Am Coll Toxicol 10:661–669

    Article  Google Scholar 

  • Moss AJ (1999) The QT interval and torsade de pointes. Drug Saf 21:5–10

    Article  PubMed  CAS  Google Scholar 

  • Murphy DJ (1994) Safety pharmacology of the respiratory system: techniques and study design. Drug Dev Res 32:237–246

    Article  CAS  Google Scholar 

  • Murphy DJ (2002) Assessment of respiratory function in safety pharmacology. Fundam Clin Pharmacol 16:183–196

    Article  PubMed  CAS  Google Scholar 

  • Olsen H, Betton G, Robimson D, Thomas K, Monro A, Kolaja G, Lilly P, Sanders J, Sipes G, Braken W, Dorato M, Van Deun K, Smith P, Berger B, Heller A (2000) Concordance of the toxicity of pharmaceuticals in humans and animals. Regul Toxicol Pharmacol 32:56–67

    Article  Google Scholar 

  • Omosu M, Komine I, Becker RH, Schölkens BA (1988) General pharmacology of Ramipril. Arzneimittel Forsch Drug Res 38:1309–1317

    CAS  Google Scholar 

  • Porsolt RD, Lemaire M, Durmuller N, Roux S (2002) New perspectives in CNS safety pharmacology. Fundam Clin Pharmacol 16:197–207

    Article  PubMed  CAS  Google Scholar 

  • Porsolt RD, Picard S, Lacroix P (2005) International safety pharmacology guidelines (ICH S7A and S7B): where do we go from here? Drug Dev Res 64:83–89

    Article  CAS  Google Scholar 

  • Proakis AG (1994) Regulatory considerations on the role of general pharmacology studies in the development of therapeutic agents. Drug Dev Res 32:233–236

    Article  Google Scholar 

  • Pugsley MK, Curtis MJ (2007) Safety pharmacology methods: anticipating the transition from long QT (LQTS) to short QT syndromes (SQTS)? J Pharmacol Toxicol Methods 56:87–90

    Article  PubMed  CAS  Google Scholar 

  • Pugsley MK, Authier S, Curtis MJ (2008) Principles of safety pharmacology. Br J Pharmacol 154:1382–1399

    Article  PubMed  CAS  Google Scholar 

  • Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, Siegl PKS, Strang I, Sullivan AT, Wallis R, Camm AJ, Hammond TG (2003) Relationships between preclinical cardiac electrophysiology clinical QT interval prolongation, and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res 58:1–44

    Article  Google Scholar 

  • Regan N, Sutton MR, Waldron G, Alexandrou A (2008) Multiple mechanisms of QTc shortening. J Pharmacol Toxicol Methods 58:158

    Article  Google Scholar 

  • Ross JF, Mattsson JL, Fix AS (1998) Expanded clinical observations in toxicology studies: historical perspectives and contemporary issues. Regul Toxicol Pharmacol 28:17–26

    Article  PubMed  CAS  Google Scholar 

  • Sarlo K, Clark ED (1995) Evaluating chemicals as respiratory allergens: using a tier approach for risk assessment. Methods Immunotoxicol 2:411–426

    CAS  Google Scholar 

  • Shah RR (2005a) Drugs, QT interval prolongation and ICH E14. Drug Saf 28:115–125

    Article  PubMed  Google Scholar 

  • Shah RR (2005b) Drugs, QTc interval prolongation and final ICH E14 guideline. Drug Saf 28:1009–1028

    Article  PubMed  CAS  Google Scholar 

  • Shah RR (2010) Drug-induced QT interval shortening: potential harbinger of proarrythmia and regulatory perspectives. Br J Pharmacol 159:58–69

    Article  PubMed  CAS  Google Scholar 

  • Spence S, Soper K, Hoe C-M, Coleman J (1998) The rate-corrected QT interval of conscious beagle dogs: a formula based on analysis of covariance. Toxicol Sci 45:247–258

    Article  PubMed  CAS  Google Scholar 

  • Thomas SHL (1994) Drugs, QT interval abnormalities and ventricular arrhythmias. Adverse Drug React Toxicol Rev 13:77–102

    PubMed  CAS  Google Scholar 

  • Vargas HM, Bass AS, Breidenbach A, Feldman HS, Gintant GA, Harmer AR, Heath B, Hoffmann P, Lagrutta A, Leishman D, McMayhon N, Mittelstadt S, Polonchuk L, Pugsley MK, Salata JJ, Valentin J-P (2008) Scientific review and recommendations on preclinical cardiovascular safety evaluation of biologics. J Pharmacol Toxicol Methods 58:72–76

    Article  PubMed  CAS  Google Scholar 

  • Viskin S (1999) Long QT syndromes and torsade de pointes. Lancet 354:1625–1633

    Article  PubMed  CAS  Google Scholar 

  • Wakefield ID, Pollard C, Redfern WS, Hammond TG, Valentin J-P (2002) The application of in vitro methods to safety pharmacology. Fundam Clin Pharmacol 16:209–218

    Article  PubMed  CAS  Google Scholar 

  • Webster R, Leischman D, Walker D (2002) Towards a drug concentration effect relationship for QT prolongation and torsades de pointes. Curr Opin Drug Discov Devel 5:116–126

    PubMed  CAS  Google Scholar 

  • Williams PD (1990) The role of pharmacological profiling in safety assessment. Regul Toxicol Pharmacol 12:238–252

    Article  PubMed  CAS  Google Scholar 

  • Williams PD, Bass AS (2003) Safety pharmacology: a practical guide. TherImmune Research, Gaithersburg

    Google Scholar 

  • Zbinden G (1979) Pharmacological methods in toxicology. Pergamon, Elmsford, p 613

    Google Scholar 

  • Zbinden G (1984) Neglect of function and obsession with structure in toxicity testing. In: Proceedings of the 9th international congress of pharmacology, vol 1, pp 43–49

    Google Scholar 

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Authors and Affiliations

  1. Business Development Consultant, CorDynamics, Altstadt 19, Dieburg, Germany

    Dr. Franz J. Hock

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  1. Dr. Franz J. Hock
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Correspondence to Franz J. Hock .

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Editors and Affiliations

  1. Sanofi Pharma Deutschland GmbH, A company of the Sanofi-Aventis Group Industriepark Hoechst, Frankfurt am Main, Germany

    Jochen Maas

  2. Dieburg, Germany

    Franz J. Hock

  3. Idstein, Germany

    Dieter Mayer

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Hock, F.J. (2013). Status of Safety Pharmacology and Present Guidelines. In: Vogel, H.G., Maas, J., Hock, F.J., Mayer, D. (eds) Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-25240-2_1

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