Safety and secondary pharmacology: Successes, threats, challenges and opportunities

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    lecy, gl noy oisk as an

    New Creasedsafetyeveloproximaer et ae mainawals

    ADRs fall into 5 types (A to E), out of which the type A represents ~75%

    studies are extremely safe (Table 2). This is related to the fact that

    for safety pharmacology as it relates to the increasing development

    Journal of Pharmacological and Toxicological Methods 58 (2008) 7787

    Contents lists available at ScienceDirect

    Journal of Pharmacological a

    l seof all cases (Redfern, Wakeeld, Prior, Hammond & Valentin, 2002).The type A ADRs are dose-dependent and predictable from primary,secondary and safety pharmacology. A signicant proportion of thesetoxicities is functional in nature and, therefore, should be predictablefrom a thorough assessment of SSP. For instance, the prominence ofarrhythmias as a reason for drug discontinuation (approximately halfof the 19% reported by Stephens, 2004) probably reects the concernfor drug-induced Torsades de Pointes (TdP) type arrhythmias and the

    of biologics and points out how difcult it is to lay out any generalexamples of typical non-clinical safety programs for biologics. Never-theless, recent investigations on the mechanisms of the TGN-1412-mediated cytokine storm will enable to develop novel procedures toimprove non-clinical safety testing of immunomodulatory therapeutics(Stebbings et al., 2007). Meanwhile, this serious AE has lead to thedevelopment and implementation of more stringent regulatory guide-lines for high-risk medicinal products (Anon., 2007).effort, froma safety pharmacology perspectiveOne of the primary objectives of the non-cl

    to dene the starting dose in humans, in r

    Corresponding author.E-mail address:

    1056-8719/$ see front matter 2008 Elsevier Inc. Alldoi:10.1016/j.vascn.2008.05.007ities ranked top in theseug withdrawals. Human

    serious AEs observed with the CD28 agonist antibody TGN-1412 in aphase I study in early 2006 (Anon., 2006; Table 2) opens new challengesreviews, accounting globally for 926% of drworldwide market (Fung et al., 2001; Stephens, 2004; Table 1).Cardiovascular, CNS and hepatic-related toxicbeing launched has signicantly decperiod, both non-clinical and clinicalcause of drug attrition during clinical dof marketed drugs; accounting for appdiscontinuation (Kennedy, 1997; Lass2004). Recent reviews have explored threactions (ADRs)-related drugs withdrhas remained the majorment and of withdrawaltely 35 to 40% of all drugl., 2002; Kola & Landis,causes for adverse drug

    from either the U.S.A. or

    studies are usually related to the procedure (e.g., needle puncture,headache secondary to caffeine deprivation) and/or to the primarypharmacology of the drug (i.e., mechanism of action). Interestingly, themain ADRs reported are often not detected by toxicology/pharmacologystudies (e.g., headache, dizziness, nausea). Thus non-clinical safetyevaluation to support Phase I is effective; compounds that do get intomando so safely. However,while this holds true for smallmolecules, theincreased (+20%) and, the number of hemical Entities (NCEs)(30%). Over the same

    detected earlier in non-clinical safety studies and therefore not pro-gressed into clinical development. Therefore, AEs reported during FTIMdecade, despite signicant R&D investment (+70%), reecting the in-crease in sales (+120%), the overall drug development time has compounds with potentially dangerous adverse events (AEs) areAppraisal of state-of-the-art

    Safety and secondary pharmacology: Succ

    Jean-Pierre Valentin , Tim HammondSafety Assessment UK, AstraZeneca, Mereside, Alderley Park, Maccleseld, Cheshire, SK10 4

    A B S T R A C TA R T I C L E I N F O

    Article history:Received 19 March 2008Accepted 19 May 2008

    Keywords:Safety pharmacologyPharmacological prolingAdverse drug reactionsQT interval prolongation

    This review summarises theSafety Pharmacology Societbehind the need for optimaand Secondary Pharmacologof adopting an integrated rnally the future challenge

    1. Rationale for a non-clinical safety and secondary pharmacology(SSP) testing

    A pharmaceutical industry survey revealed that, over the last

    j ourna l homepage: www.e, to detect such an effect.inical safety evaluation iselation to the potential

    m (J.-P. Valentin).

    rights, threats, challenges and opportunities

    United Kingdom

    ture of Dr Tim Hammond, recipient of the Distinguished Service Award of theiven on 20 September 2007 in Edinburgh. The lecture discussed the rationalen-clinical Safety and Secondary Pharmacology testing; the evolution of Safetyver the last decade; its impact on drug discovery and development; the valuessessment approach; the translation of non-clinical ndings to humans andd opportunities facing these disciplines.

    2008 Elsevier Inc. All rights reserved.

    therapeutic concentration, and the range of unacceptable toxicological/pharmacological side effects. A report published in 2005 under theauspice of the British Academy of Medical Sciences (Anon, 2005a)showed that healthy volunteer single dose rst time in man (FTIM)

    nd Toxicological Methods

    v ie locate / jpharmtox2. Evolution of safety and secondary pharmacology

    Over the last decade, reecting increasing regulatory concerns,there has been an increased number and scope of regulatory guidancedocuments referring entirely or in part to safety pharmacology (Fig.1).One would intuitively expect that scientic and technological

  • advancements should drive and inuence the regulatory environment.In fact, looking at the trend in the number of publications on QT andhERG on one hand and General Pharmacology and Safety

    Table 1Main reasons for drug discontinuation during non-clinical or clinical development, withdra

    Physiological systems

    CVS CNS Hep

    Combine non-clinical and clinical (1) 2734 14 15Incidence of ADRs associated with marketed drugs (2) 35 56 11Incidence of ADRs associated with marketed drugs (3) 15 14 Withdrawal (4) 19 12 92

    CVS, Cardiovascular; CNS, Central nervous System; GI, Gastrointestinal. Incidence (i.e., N3%) oData are based on 88 candidates discontinued between 1993 and 2006 in non-clinical or clinextracted from BioPrint. Not all compound-ADR annotations include incidence data; hencpatients treated in emergency departments in the U.S.A. in 2004 and 2005. (4) Drug withdraCombining Cardiovascular and Haematology. Combining central and peripheral nervo

    78 J.-P. Valentin, T. Hammond / Journal of Pharmacological and Toxicological Methods 58 (2008) 7787Pharmacology on the other hand, it becomes evident that the rise innumber of publication follows, rather than precede, the emergence ofregulatory documents (i.e., CPMP, Anon., 1997 and ICH S7A, Anon.,2000, respectively; Fig. 2).

    During the drug discovery process, 3 types of pharmacologystudies are conducted; primary, secondary and safety pharmacologystudies. Primary pharmacodynamic studies aim at investigating themode of action and/or effects of a substance in relation to its desiredtherapeutic target. Secondary pharmacodynamic studies aimed atinvestigating the mode of action and/or effects of a substance notrelated to its desired therapeutic target, whereas safety pharmacologystudies aimed at investigating the potential undesirable pharmaco-dynamic effects of a substance on physiological functions in relation toexposure in the therapeutic range and above. Safety pharmacody-namic effects may result from activity at the primarymolecular target,secondary targets or non-specic interactions (Bowes, Rolf & Valentin,2006; Fig. 3). Hence, having a good understanding of the overallpharmacology of the drug is important in designing an optimal safetypharmacology programme. As to achieve the main objectives of safetypharmacology, SSP studies can be aligned and applied to the differentphases of drug discovery and development (Anon., 2000; Valentin &Hammond, 2006). More specically, safety pharmacology studies aim(i) to identify undesirable pharmacodynamic properties of a substancethat may have relevance to its human safety; (ii) to evaluate adversepharmacodynamic and/or pathophysiological effects of a substanceobserved in toxicology and/or clinical studies; (iii) to investigate themechanism of the adverse pharmacodynamic effects observed and/orsuspected. The impact of SSP in relation to these objectives referprimarily to (i) Hazard Identication and Elimination, (ii) RiskAssessment and (iii) Risk Management and Mitigation, respectively(Table 3).

    Table 2

    Risks to healthy volunteers in Phase I clinical research trials

    Year Number ofvolunteers

    Moderatelysevere AE

    Potentially life-threatening AE

    Deaths References

    196577 29,162 58 (0.2%) 0 Zarafonetis al. (1978)

    1980 1 Kolata G.B. (1980)1983 1 Darragh A. et al.

    (1985)1984 1 Anon. (1985)198687 8163 45 (0.55%) 3 (0.04%) 0 Orme M. et al.

    (1989)198695 1015 43 (3%) 0 0 Sibille M. et al.

    (1998)2000 1 McCarthy M. (2001)2006 6 6 (100%) 0 Anon. (2006)

    AE, Adverse Event. Adapted from Redfern et al. (2002).3. Successes of safety and secondary pharmacology

    In this section we shall provide examples of application of SSPapproaches to the different phases of drug discovery and developmentand highlight their impact in the discovery/development process.

    3.1. Hazard identication and elimination

    Although hazard can be identied at any stage of the discovery/development process, during the early drug discovery phases SSP isprimarily applied, to hazard identication and wherever possible tohazard eradication or elimination. Approaches that are being usedshould be amenable to the chemistry make-test cycle, by having rapidturn around time and low compound requirements. Consequently, th