JPM-06207; No of Pages 5 Journal of Pharmacological and Toxicological Methods xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Journal of Pharmacological and Toxicological Methods journal homepage: www.elsevier.com/locate/jpharmtox

1

Original article

4Q2

Michael K. Pugsley a,⁎, Jill A. Dalton b, Simon Authier c, Michael J. Curtis d a

9

a r t i c l e

10 11 12 13

Article history: Received 5 August 2014 Accepted 6 August 2014 Available online xxxx

Drug Safety Sciences, Janssen Research & Development, LLC., 1000 Route 202 South, Raritan, NJ, 00869, USA Safety Pharmacology, MPI Research, Inc., 54943 North Main St., Mattawan, MI 49071-9399, USA CiToxLAB Research Inc., 445 Armand Frappier, Laval, QC H7V 4B3, Canada d Cardiovascular Division, Rayne Institute, St Thomas' Hospital, London SE17EH, UK b

i n f o

a b s t r a c t

D

P

“What do you know about Safety Pharmacology?” This is the question that was asked in 2000 with the inception of the Safety Pharmacology Society (SPS). There is now a widespread awareness of the role of safety pharmacology in drug discovery and increasing awareness among the wider community of methods and models used in the assessment of the core battery required set of safety studies. However, safety pharmacology does not stop with core battery studies. New methods are intensively sought in order to achieve a swifter and more reliable assessment of adverse effect liability. The dynamics of the discipline and method expansion are reflected in the content of this issue of the Journal of Pharmacological and Toxicological Methods (JPTM). We are into the second decade of publishing on safety pharmacology methods and models, reflected by the annual themed issue in JPTM, and on willingness of investigators to embrace new technologies and methodologies. This years' themed issue is derived from the annual Safety Pharmacology Society (SPS) meeting, held in Rotterdam, The Netherlands, in 2013. © 2014 Published by Elsevier Inc.

14

T

E

15

26

E

29

1. Overview

32 33

As with the previous JPTM SPS themed issues, papers consider some exciting new applications with attempts to validate in vitro and in vivo safety pharmacology models. Surprisingly (since historically safety pharmacology method innovation has been focused on cardiac adverse drug reactions (ADRs)), the majority of the articles in this issue probe CNS drug safety methods. Topics range from the introduction of behavioral test methods into sub-chronic (≤3 month) regulatory toxicology studies to the characterization of the response of non-human primate sleep architecture and EEG activity to known pharmacological agents (caffeine, amphetamine and diazepam) using telemetry-based polysomnography. Likewise, the use of telemetry video electroencephalography (EEG) in rats, dogs and non-human primates is discussed as a method in ‘follow-up’ safety pharmacology seizure liability assessments for new chemical entities (NCE). Finally, the utilization of both in vitro (hippocampal slices) and in vivo (rats implanted with EEG electrodes for monitoring via telemetry) methods were complementary in characterizing the seizure potential of an NCE. Respiratory articles include a review that discusses the value and utility of the methods and measurement endpoints currently available for assessing respiratory function to help optimize the design of respiratory safety pharmacology studies and

42 43 44 45 46 47 48 49 50 51

Q3

R

N C O

40 41

U

38 39

R

31

36 37

16 17 18 19 20 21 22 Q4 23 24 25

C

30 28 27

34 35

R O

c

O

5 6 7 8

F

3Q1

Safety pharmacology in 2014: New focus on non-cardiac methods and models

2

⁎ Corresponding author at: Global Safety Pharmacology, Janssen Research & Development, LLC, 1000 Route 202 South, Raritan, NJ 00869, USA. Tel.: +1 908 927 4148. E-mail address: [email protected] (M.K. Pugsley).

readers are introduced to airwave oscillometry, which appears to be a promising non-invasive methodology to measure respiratory mechanics in conscious animals. In the day and age of stem cells and their possible future application to drug safety assessment we include an article that investigates the actions of E-4031, verapamil, dofetilide, pentamidine, terfenadine, quinidine and nifedipine on action potentials (AP) and ion currents recorded from adult human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). hiPSC-CM are shown to display excellent sensitivity to ion channel blockers resulting in characterized changes in the electrophysiology of the AP suggesting use as a screening method for NCEs. Another article predicts the result of the human clinical Thorough QT (TQT) study using in silico methods applied to data derived from multiple ion channel screens. In silico AP simulations were conducted using many models and findings suggest that this approach is a useful complementary tool in cardiac safety assessment. Lastly, also included in this issue is a comprehensive review on cardiovascular pressure measurement and its application to safety assessment studies. The article nicely highlights the technology requirements and discusses the potential errors that can be made from such recordings.

52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71

2. Methods used to assess CNS function in the safety pharmacology 72 assessment of a new chemical entity (NCE) 73 When compared to the cardiovascular system the other required 74 vital core battery components, the CNS and respiratory organ systems, 75

http://dx.doi.org/10.1016/j.vascn.2014.08.004 1056-8719/© 2014 Published by Elsevier Inc.

Please cite this article as: Pugsley, M.K., et al., Safety pharmacology in 2014: New focus on non-cardiac methods and models, Journal of Pharmacological and Toxicological Methods (2014), http://dx.doi.org/10.1016/j.vascn.2014.08.004

99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 Q5 117 Q6 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141

F

O

R O

97 98

P

95 96

D

93 94

the results provided a clear template for identifying pro- and anticonvulsant activity that may be useful in CNS safety assessment of an NCE. Importantly, the authors emphasize that when seizure liability investigations are conducted, rats typically represent the ‘first-line’ model whereas Beagle dogs are generally overly sensitive to seizure susceptibility (Edmonds et al., 1979) (and are typically only used if required by regulatory authorities). Markgraf et al. (2014) described the use of in vitro and in vivo nonclinical models in the evaluation of the seizure potential of a CNStargeted NCE. They used Org 306039, a potent and selective 5-HT2c agonist that was in development for obesity as a positive control in both types of assays. The 5-HT2c receptor is associated with excitatory neurotransmission (i.e., the binding of serotonin to the receptor subtype inhibits dopamine and norepinephrine release) in the prefrontal cortex, hippocampus, hypothalamus and striatal brain regions. These receptors are reported to modulate mood and anxiety and have been in development as an ensemble target for anti-obesity and antidepression. The authors used rat hippocampal slice preparations and male SpragueDawley rats implanted with telemetry EEG recording electrodes to characterize responses to the seizure causing standard, Org 306039. Animals received either vehicle or Org 306039 (100 mg/kg, po) daily for 10 days. Org 306039 elicited a concentration-dependent increase in population spike area and number recorded from hippocampal CA1 cells, indicative of an increase in potential seizurogenic activity. Repeat dosing of Org 306039 was associated with the appearance of ‘seizurerelated’ behaviors (such as shivering, tremors and head shakes) and pre-seizure waveforms on the EEG with the observation of an overt seizure in one animal. Findings from both the hippocampal slice preparations and in vivo models appear complementary to one another when used in the characterization of the seizure potential of CNS-targeted compounds.

T

91 92

C

89 90

E

87 88

R

85 86

R

83 84

O

82

C

80 81

N

78 79

albeit important, are much less intensely explored in the context of methodological innovation. The predominance of the cardiac system in forums and scientific literature on safety pharmacology is at least partially attributable to the high impact of rare but lethal events related to this system (Curtis & Pugsley, 2012; Valentin & Hammond, 2008). Interestingly, therefore, this issue contains a variety of articles that highlight innovative methods used to assess CNS, respiratory and systems relevant to safety assessment of an NCE. As per ICHS7A (US FDA, 2001), non-clinical safety pharmacology studies generally evaluate a single dose of test article or doses ranging from efficacy to low multiples above efficacy, which impinge upon but do not result in overt end organ toxicity (as this can limit interpretation of the drug-induced pharmacological effects on cardiovascular (CV), respiratory and CNS function). Safety pharmacology studies are conducted in accordance with good laboratory practice (GLP) and use the most relevant state of the art methods to assess CV changes, respiratory function or CNS liability while ensuring that optimal study conditions are considered (Guth et al., 2009; Pugsley, Authier, & Curtis, 2008). The assessment of CV, respiratory and CNS effects of an NCE in toxicology studies, however, is limited. Because toxicology studies (acute, subchronic and chronic) are critical in assessing the end organ toxicological response of an NCE, a conservative stance has existed with respect to modification of study design and application of new technologies and methodologies (see Authier, Vargas, Curtis, Holbrook, & Pugsley, 2013 for SPS survey of best practices on this topic). Toxicology studies do not usually involve the use of animals instrumented for telemetry monitoring of CV function because CV assessment is ancillary when the focus is on toxicity. However, Golozoubova et al. (2014) incorporated a safety pharmacology behavioral (i.e., modified Irwin screen) test into a standard sub-chronic (3 month) toxicology study with a view to reduction of animal use (3 Rs principles) by replacing stand-alone safety pharmacology experiments in the assessment of an NCE. The authors used two strains of rat (Wistar and Sprague-Dawley), of both genders, and found little differences in response; however, they observed that with time, individual animal variability actually increased with repeated measurements. The authors suggest that researchers conducting such studies need to consider study design and animal group size if they are to integrate safety pharmacology endpoints into toxicology studies (see article by Pugsley, Towart, Authier, Gallacher, & Curtis, 2010). This resonates with other emerging wider pharmacological methodological guidance (Curtis et al., 2013). Authier et al. (2014a, 2014b) applied the clinical diagnostic method of polysomnography, i.e., the comprehensive recording of brain (electroencephalogram, EEG), eye movements (electro-oculogram, EOG) and muscle activity (electromyogram, EMG) during sleep to nonhuman primates (NHP). Use of such methods is hoped to enhance the translational potential of drug-induced changes in sleep architecture in non-clinical species to patients. The authors characterized the responses of known pharmacological agents (d-amphetamine, diazepam and caffeine) that affect sleep structure and EEG activity in NHP (Macaca fascicularis) using telemetry-based polysomnography. Animals in the study were instrumented with telemetry transmitters for continuous recording of EEG, EOG and EMG monitoring (combined with video). At the doses tested all observations were similar to those previously reported for the pharmacological effects observed in humans suggesting that telemetry monitoring of EEG, EOG and EMG in the NHP could be a useful non-clinical approach with which to investigate drugs with the potential to induce sleep disturbance. Bassett, Troncy, Pouliot, et al. (2014) examined non-clinical seizure liability using intravenous pentylenetetrazole (PTZ) in combination with pharmacological agents that alter seizure thresholds and induce clonic convulsions in EEG telemetered Cynomolgus monkeys, Beagle dogs and Sprague-Dawley rats. The authors outline and evaluate the premonitory clinical signs in each species that include altered physical activity, enhanced tremors, ataxia, emesis and myoclonus. Drugs tested included amphetamine, caffeine, yohimbine and phenobarbital and

U

76 77

M.K. Pugsley et al. / Journal of Pharmacological and Toxicological Methods xxx (2014) xxx–xxx

E

2

142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172

3. Recommendations and novel methods used to assess respiratory function

173 174

Core battery safety pharmacology respiratory studies focus on drug effects on basic pulmonary function (Pugsley et al., 2008). The standard model utilizes whole body plethysmography recording in conscious rodents (Murphy, 2005). In this issue of the Journal, Murphy (2014) describes, in a comprehensive review article, the variety of methods and pulmonary functional endpoints that can be used in the evaluation of an NCE for effects on respiratory function. In order to conform to the ICH S7A guidelines, respiratory safety pharmacology studies generally are conducted using conscious animal models and usually assess pulmonary ventilation including respiratory rate (RR), tidal volume (Vt) and arterial blood gases — standard variables. These measures describe pulmonary ventilation (or minute volume, MV), frequency of breathing (RR), and depth of breathing (Vt) and are surrogates for adequate gas exchange and tissue oxygenation (Murphy, 2013). However, as Murphy discusses, other variables that can be used to provide mechanistic insight or identify site of drug action, should also be considered for incorporation. These variables include inspiratory and expiratory times, flows (and pauses) as well as apneic time. However, measures of pulmonary ventilation only assess drug effects on the respiratory pumping apparatus and do not assess other components of the respiratory system such as exchange. These are best characterized by measuring drug effects on airway patency, gas diffusion capacity and lung elastic recoil. These additional measures are not commonly determined in standard safety pharmacology respiratory studies. It is useful to consult the Lindgren et al. (2008) survey that benchmarked safety pharmacology best practice for use in regulatory package submissions. When respiratory study endpoints were assessed 100% of safety assessment investigator respondents (N = 64–66) measured respiratory rate and 98% measured tidal/minute volume; however, only 39% measured compliance/resistance and only 16% measured additional endpoints including blood gases, peak inspiratory and expiratory flow rates, inspiratory and

175 176

Please cite this article as: Pugsley, M.K., et al., Safety pharmacology in 2014: New focus on non-cardiac methods and models, Journal of Pharmacological and Toxicological Methods (2014), http://dx.doi.org/10.1016/j.vascn.2014.08.004

177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205

M.K. Pugsley et al. / Journal of Pharmacological and Toxicological Methods xxx (2014) xxx–xxx

227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243

244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 Q7 Q8 259 260 261 262 263 264 265 266 267 268

4. In silico methods: can a mathematical model of a cardiac action potential predict the results from a human clinical Thorough QT (TQT) study? The article by Mirams et al. (2014) characterized ion channel blockade for a series of ion channels that are responsible for genesis of the cardiac action potential (hERG or Kv11.1 channel; L-type calcium or CaV1.2 channel, inward sodium or NaV1.5 channel, KCNQ1/MinK or Kv7.1 (KvLQT1) and Kv4.3/KChIP2.2 or transient outward K current) using two standard electrophysiological platforms: the IonWorks Barracuda and IonWorks Quattro high throughput screening (HTS) assay systems. The authors then used the data generated from both HTS platforms to simulate drug-mediated effects on human ventricular action potentials using several comparator mathematical simulation models. The models used included the Ten Tusscher and Panfilov (2006), Grandi, Pasqualini, and Bers (2010) and O'Hara, Virág, Varró, and Rudy (2011) models and data derived from these in silico concentrationresponse simulations were then compared to clinical TQT results for the 34 compounds tested. At the study conditions used (1 Hz pacing and channel block determined at steady-state) simulations tended to underestimate the observed QT prolongation observed in the clinic. Readers of JPTM should be cognizant of the fact that there are differences, mathematically (and hence ‘physiologically’), between the in silico methods utilized in the simulation of the cardiac action potential that could result in somewhat different drug responses to human ion channel screening data.

311

Current alternative screening models and methods under consideration by the safety pharmacology and regulatory communities for the CIPA initiative include stem cells in which hERG (IKr) as well as other cardiac ion channels such as sodium (SCN5A), calcium (Cav1.2) and additional potassium channels (IK1 and IKs) can be assessed in totality. Rather than examining human ion channel isoforms heterogeneously expressed in cell lines (such as CHO or HEK) as is currently conducted routinely in drug safety or, on the rare occasion, actually using isolated human cardiac myocytes, the community is investigating applicability of human induced pluripotent stem cells (Vidarsson, Hyllner, & Sartipy, 2010; Peng, Lacerda, Kirsch, Brown, & Bruening-Wright, 2010, see commentary by Pugsley, Authier, & Curtis, 2013). The undifferentiated human stem cell of embryonic origin (hESC) and induced pluripotent stem cell (iPSCs) of somatic origin (the latter with the potential advantage that they can be obtained from diseased patients, e.g., congenital LQTS) continue to be evaluated for all aspects of their cardiac electrophysiological potential (Tanaka et al., 2009). Gibson, Bronsona, Palmera, and Numann (2014) examined the effects of a number of diverse compounds with mixed pharmacological actions on ventricular action potentials (AP) and ionic currents recorded from adult human induced pluripotent stem cell-derived

312 313

O

F

5. Stem cells and their use in safety pharmacology

R O

225 226

P

223 224

269 270

D

221 222

The ten Tusscher and Panfilov in silico model (2006) is one in which the cardiac ventricular action potential is based upon the measurement of human APD restitution and includes an extensive description of intracellular calcium dynamics. In addition, ten Tusscher and Panfilov found that sodium channel (INa) recovery dynamics are important in the occurrence of electrical instability. Grandi et al. (2010) also developed a comprehensive mathematical model of the ventricular action potential that captured calcium handling processes and incorporate ionic currents as measured in human cells. In the development of their model they simulated basic excitation–contraction coupling phenomena and applied realistic repolarizing potassium current densities. As with most in silico models, this one relies upon the rabbit myocyte model developed previously by this group. However, differences include developing subsarcolemmal compartments where ion channels are programmed to ‘sense’ higher levels of calcium compared to the cytosol. In addition, transmural gradients for calcium handling proteins and the sodium pump were simulated and both the rapid and slow inactivating components of the transient outward potassium current (Ito) were simulated to differentiate between localization either endocardially or epicardially. O'Hara et al. (2011) developed a human ventricular cardiac AP model based upon data measured from over 100 undiseased human hearts. Components of the model were evaluated over the human range of physiological frequencies and include calcium versus voltage dependent inactivation of L-type calcium current (ICaL), kinetics for the transient outward, rapid delayed rectifier (IKr) and inward rectifier (IK1) potassium currents along with the Na+/Ca2 + exchange pump (INaCa). The authors also examined model response to rate dependence and restitution of cardiac AP duration (APD). Note that this model is referred to as the O'Hara-Rudy Dynamic (ORd) model. The results derived from this paper are an important contribution to the development of the Comprehensive In vitro Proarrhythmia Assay (CIPA) initiative currently ongoing between the pharmaceutical industry, contract research organizations and regulatory authorities (FDA) (Cavero & Holzgrefe, 2014; Gintant, 2012; Sager, Gintant, Turner, Pettit, & Stockbridge, 2014). The authors have established a data set composed of clinically used compounds which should provide much needed information to the entire scientific community regarding adoption, applicability and in silico simulation limitations in safety hazard identification as well as the nature of the data derived from HTS (vs. voltage clamp) methods subsequently used in those simulation methods.

E

219 220

T

217 218

C

215 216

E

213 214

R

212

R

210 211

N C O

208 209

expiratory time, enhanced pauses, lung sounds and pulse oximetry. As a wide range of within-breath parameters such as peak inspiratory and expiratory flow rates and inspiratory and expiratory time can be directly derived from the respiratory signal without any additional experimental work, the addition of those to the safety risk assessment could be considered as a ‘low hanging fruit’. Perhaps it is time to re-visit pulmonary function assessment in safety pharmacology studies. What, exactly, represents the most sensitive variable for detecting adverse drug reactions in the respiratory system? Why measure a basket of variables if there is no mechanism for interpreting the data array? Bassett, Troncy, Robichaud, et al. (2014) introduced a new noninvasive methodology with potential application to respiratory safety pharmacology assessment. The authors presented a means by which to measure respiratory system resistance (Rrs) in conjunction with conventional respiratory parameters (Vt, RR, MV) in conscious Beagle dogs and NHP. Airway oscillometry measurements can be performed to produce a direct, instantaneous measure of airway resistance. The method involved introducing low amplitude pressure or volume-driven oscillations into the pulmonary airflow of the animal and capturing the response. The authors used the airwave oscillometry system (tremoFlo ™ C-100 Airwave Oscillometry System) to assess drug-induced changes on Rrs before and after intravenous treatment with methacholine, a bronchoconstrictor. Not surprisingly they found that there are differential sensitivities between animal species to the effects of methacholine. Furthermore, conventional parameters such as Vt, RR and MV do not capture drug induced pulmonary pharmacodynamic changes that require a direct measure of Rrs to be identified (Murphy, 2014). In the clinic, airwave oscillometry is used in central airway obstruction patients undergoing bronchoscopy who cannot be readily assessed using standard spirometry methods (Handa et al., 2014). Note that there exists a body of recent literature that suggests that assessment of variations in airway resistance over time, rather than resistance itself, may be better predictive of certain disease patterns and measure how well a patient is being managed. Thus, airwave oscillometry appears to be a promising non-invasive methodology to enable respiratory mechanic measurements in conscious large animals, a potential valuable refinement to respiratory safety pharmacology methods with possible clinical translation potential to pulmonary disease states.

U

206 207

3

Please cite this article as: Pugsley, M.K., et al., Safety pharmacology in 2014: New focus on non-cardiac methods and models, Journal of Pharmacological and Toxicological Methods (2014), http://dx.doi.org/10.1016/j.vascn.2014.08.004

271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310

314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332

342 343 344 345

6. Novel measures of drug-induced cardiotoxicity with applicability to safety pharmacology

348

363 364

It is known that some drugs (i.e., amiodarone) are toxic for the developing embryo so the regulatory authorities contraindicate their use in pregnancy. In order to limit exposure during pregnancy the FDA has established five categories that indicate the potential for a drug to cause birth defects if used during pregnancy. The categories are determined by the risk to benefit ratio and available data. The paper by Ritchie, Haaland Svensson, Nilsson, and Webster (2014) characterizes the cardiotoxicity, i.e., bradycardic potential of several drugs (such as citalopram, amiodarone and dofetilide) with this known pharmacological action therapeutically in rat embryos cultured in human serum or a protein free solution. This is an interesting assay, in contrast to the in vitro human placental model (see Hutson, 2011) that is used to evaluate transplacental effects of new compounds on the fetus. Interestingly, the authors found greater than expected reductions in heart rates for drugs solubilized in human sera than predicted; thus, toxicity testing using protein-free in vitro methods may not actually capture accurate safety margins predicted when calculated using protein binding values.

365 366

7. Technological aspects to be considered in the recording of cardiovascular pressure

367 368

The maintenance of blood pressure (BP) is dependent upon a number of intrinsic factors such as stroke volume and heart rate, circulating hormones such as renin-angiotensin and vasopressin, autonomic reflexes such as baroreceptors present in the aortic arch and carotid sinuses as well as sensory nerve fibers that relay signals to the medulla and renal function where appropriate excretion and retention of extracellular fluid are required and maintained by aldosterone and antidiuretic hormone (ADH). Thus, the significance of the individual mechanisms responsible for maintenance of BP is likely different between species such that even small changes in hemodynamics, especially after chronic drug treatment can be of clinical concern. This is a topic that has not really been discussed in safety pharmacology. Sarazan (2014) writes a comprehensive review of the methods and technology issues involved in the measurement of BP. This fascinating article outlines the nature of the BP pulse, a periodic signal that is both tonic and phasic in nature. Both direct and indirect systems used in BP measurement are discussed with a focus on direct measures (i.e., transducers) with an overview of the advantages and limitations to the devices used which can affect the fidelity of the recording. Discussed are rare topics in the realm of safety pharmacology such as hydrostatic pressure effects from intravascular blood, recording stability (drift) of the sensor over time and frequency response of the sensor. Readers should have a better sense of the actual components involved in BP measurement which will provide information regarding the optimal conditions needed to assess drug effects on the BP signal thus, hopefully, reducing recording errors and limiting inaccurate drug responses.

369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392

C

E

361 362

R

359 360

R

357 358

O

355 356

C

353 354

N

351 352

U

349 350

Conflicts of interest

409

396 397 398 399 400 401 402 403 404 405 406 Q9 Q10 407 Q11 408 Q12

None of the authors have any conflicts of interest, other than their 410 employment in a commercial pharmaceutical companies (MKP) or 411 contract research organization (JAD, SA). 412 References

Authier, S., Bassett, L., Pouliot, M., Rachalski, A., Troncy, E., Paquette, D., et al. (2014a). Effects of amphetamine, diazepam and caffeine on polysomnography (EEG, EMG, EOG)-derived variables measured using telemetry in Cynomolgus monkeys. Journal of Pharmacological and Toxicological Methods, 70, 86–93. Authier, S., Bassett, L., Pouliot, M., Rachalski, A., Troncy, E., Paquette, D., et al. (2014b). Effects of amphetamine, diazepam and caffeine on polysomnography (EEG, EMG, EOG)-derived variables measured using telemetry in Cynomolgus monkeys. Journal of Pharmacological and Toxicological Methods (in this issue). Authier, S., Vargas, H. M., Curtis, M. J., Holbrook, M., & Pugsley, M. K. (2013). Safety pharmacology investigations in toxicology studies: An industry survey. Journal of Pharmacological and Toxicological Methods, 68, 44–51. http://dx.doi.org/10.1016/j. vascn.2013.05.002. Bassett, L., Troncy, E., Pouliot, M., Paquette, D., Ascah, A., & Authier, S. (2014a). Telemetry video-electroencephalography (EEG) in rats, dogs and non-human primates: Methods in follow-up safety pharmacology seizure liability assessments. Journal of Pharmacological and Toxicological Methods, 70, 62–65. Bassett, L., Troncy, E., Robichaud, A., Schuessler, T. F., Pouliot, M., Ascah, A., et al. (2014b). Non-invasive measure of respiratory mechanics and conventional respiratory parameters in conscious large animals by high frequency airwave oscillometry. Journal of Pharmacological and Toxicological Methods, 70, 62–65. Bassett, L., Troncy, E., Robichaud, A., Schuessler, T. F., Pouliot, M., Ascah, A., et al. (2014e). Non-invasive measure of respiratory mechanics and conventional respiratory parameters in conscious large animals by high frequency airwave oscillometry. Journal of Pharmacological and Toxicological Methods (in this issue). Cavero, I., & Holzgrefe, H. (2014). Comprehensive In vitro Proarrhythmia Assay, a novel in vitro/in silico paradigm to detect ventricular proarrhythmic liability: A visionary 21st century initiative. Expert Opinion on Drug Safety, 13, 745–758. Curtis, M. J., Hancox, J. C., Farkas, A., Wainwright, C. L., Stables, C. L., Saint, D. A., et al. (2013). The Lambeth Conventions (II): Guidelines for the study of animal and human ventricular and supraventricular arrhythmias. Pharmacology and Therapeutics, 139, 213–248. Curtis, M. J., & Pugsley, M. K. (2012). Attrition in the drug discovery process: Lessons to be learned from the safety pharmacology paradigm. Expert Opinion in Clinical Pharmacology, 5, 237–240. Edmonds, H. L., Jr., Hegreberg, G. A., vanGelder, N. M., Sylvester, D. M., Clemmons, R. M., & Chatburn, C. G. (1979). Spontaneous convulsions in Beagle dogs. Federation Proceedings, 38, 2424–2428. Gibson, J. K., Bronsona, J., Palmera, C., & Numann, R. (2014). Adult human stem cellderived cardiomyocytes detect drug-mediated changes on action potentials. Journal of Pharmacological and Toxicological Methods (in press). Gintant, G. (2012). Ions, equations and electrons: The evolving role of computer simulations in cardiac electrophysiology safety evaluations. British Journal of Pharmacology, 167, 929–931. Golozoubova, V., Brodersen, T. K., Klastrup, S., Oksama, M., Løgsted, J., & Makin, A. (2014). Repeated measurements of motor activity in rats in long-term toxicity studies. Journal of Pharmacological and Toxicological Methods. http://dx.doi.org/10.1016/j. vascn.2014.06.007. Grandi, E., Pasqualini, F. S., & Bers, D. M. (2010). A novel computational model of the human ventricular action potential and Ca transient. Journal of Molecular and Cellular Cardiology, 48, 112–121. Guth, B. D., Bass, A. S., Briscoe, R., Chivers, S., Markert, M., Siegl, P. K., et al. (2009). Comparison of electrocardiographic analysis for risk of QT interval prolongation using

T

346 347

394 395

F

340 341

Safety pharmacology continues to seek to provide validation and refine methods for use in preclinical hazard detection of NCE ADR liability. It does so in accordance with the scientific methods that rapidly progress with technology advances for functional measures. Additionally safety pharmacology seeks to organize the strategy of implementation of methods according to the guidance issued by the ICH while aiming to maximize translational value of the data acquired in hope of better predictivity in drug development. At the same time, through publication of its works, it seeks to inform the decision making of the ICH. The discipline remains in evolution and coverage of new aspects of safety is certain to expand to provide better guidance in the next few years. We note that two of the papers in this themed issue were inadvertently published early (Authier et al., 2014a, 2014b; Bassett et al., in this issue) and have been reprinted (Authier et al., 2014a, 2014b; Bassett et al., in this issue) here where they were intended to appear.

O

339

393

R O

337 338

8. Summary

P

335 336

cardiomyocytes (iCell® hiPSC-CM). The compounds tested included E-4031, dofetilide, nifedipine, terfenadine, quinidine, verapamil and acute and chronic (24 h) pentamidine. The authors examined standard study endpoints including AP duration (APD60 and APD90), resting membrane potential, the maximum rate of ventricular depolarization and AP amplitude as well as determined the IC50 values for E-4031 and nifedipine using a gramicidin-perforated patch voltage clamp method for channel block. This article shows the value of determining drug effects on the cardiac AP derived from induced pluripotent stem cell cardiomyocytes (hiPSC-CM) in safety pharmacology. The findings are interesting and relevant to the current safety pharmacology arena as they reflect how drugs can interact with various ion channels simultaneously rather than being assessed using single ion channel assays.

D

333 334

M.K. Pugsley et al. / Journal of Pharmacological and Toxicological Methods xxx (2014) xxx–xxx

E

4

Please cite this article as: Pugsley, M.K., et al., Safety pharmacology in 2014: New focus on non-cardiac methods and models, Journal of Pharmacological and Toxicological Methods (2014), http://dx.doi.org/10.1016/j.vascn.2014.08.004

413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 Q13 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 Q14 452 453 454 455 456 457 458 459 460 461 462 463 464 465

M.K. Pugsley et al. / Journal of Pharmacological and Toxicological Methods xxx (2014) xxx–xxx

Pugsley, M. K., Authier, S., & Curtis, M. J. (2008). Principles of safety pharmacology. British Journal of Pharmacology, 154, 1382–1399. Pugsley, M. K., Authier, S., & Curtis, M. J. (2013). Back to the future: Safety pharmacology methods and models in 2013. Journal of Pharmacological and Toxicological Methods, 68, 1–6. Pugsley, M. K., Towart, R., Authier, S., Gallacher, D., & Curtis, M. J. (2010). Non-clinical models: Validation, study design and statistical consideration in safety pharmacology. Journal of Pharmacological and Toxicological Methods, 62, 1–3. Ritchie, H. E., Haaland Svensson, C., Nilsson, M. F., & Webster, W. S. (2014). A comparison of drug-induced cardiotoxicity in rat embryos cultured in human serum or protein free media. Journal of Pharmacological and Toxicological Methods. http://dx.doi.org/ 10.1016/j.vascn.2014.07.008. Sager, P. T., Gintant, G., Turner, J. R., Pettit, S., & Stockbridge, N. (2014). Rechanneling the cardiac proarrhythmia safety paradigm: A meeting report from the Cardiac Safety Research Consortium. American Heart Journal, 16, 292–300. Sarazan, R. D. (2014). Cardiovascular pressure measurement in safety assessment studies: Technology requirements and potential errors. Journal of Pharmacological and Toxicological Methods. http://dx.doi.org/10.1016/j.vascn.2014.06.003. Tanaka, T., Tohyama, S., Murata, M., Nomura, F., Kaneko, T., Chen, H., et al. (2009). In vitro pharmacologic testing using human induced pluripotent stem cell-derived cardiomyocytes. Biochemical and Biophysical Research Communications, 385, 497–502. Ten Tusscher, K. H. W. J., & Panfilov, A. V. (2006). Alternans and spiral breakup in a human ventricular tissue model. American Journal of Physiology, 291, H1088–H1100. US FDA (2001). ICHS7A: Safety pharmacology studies for human pharmaceuticals. Federal Register, 66, 36791–36792. Valentin, J. P., & Hammond, T. (2008). Safety and secondary pharmacology: Successes, threats, challenges and opportunities. Journal of Pharmacological and Toxicological Methods, 58, 77–87. Vidarsson, H., Hyllner, J., & Sartipy, P. (2010). Differentiation of human embryonic stem cells to cardiomyocytes for in vitro and in vivo applications. Stem Cell Reviews, 6, 108–120.

R O

O

F

safety pharmacology and toxicological studies. Journal of Pharmacological and Toxicological Methods, 60, 107–116. Handa, H., Huang, J., Murgu, S. D., Mineshita, M., Kurimoto, N., Colt, H. G., et al. (2014). Assessment of central airway obstruction using impulse oscillometry before and after interventional bronchoscopy. Respiratory Care, 59, 231–240. Hutson, J. R. (2011). Prediction of placental drug transfer using the human placental perfusion model. Journal of Population Therapeutics and Clinical Pharmacology, 18, e533–e543. Lindgren, S., Bass, A. S., Briscoe, R., Bruse, K., Friedrichs, G. S., Kallman, M. -J., et al. (2008). Benchmarking safety pharmacology regulatory packages and best practice. Journal of Pharmacological and Toxicological Methods, 58, 99–109. Markgraf, C., DeBoer, E., Zhai, J., Cornelius, L., Zhou, Y. Y., & Macsweeney, C. (2014). Assessment of seizure liability of Org 306039, a 5-HT2c agonist, using hippocampal brain slice and rodent EEG telemetry. Journal of Pharmacological and Toxicological Methods (in press). Mirams, G. R., Davies, M. R., Brough, S. J., Cui, Y., Gavaghan, D. J., & Abi-Gerges, N. (2014). Prediction of thorough QT study results using action potential simulations based on ion channel screens. Journal of Pharmacological and Toxicological Methods. http://dx. doi.org/10.1016/j.vascn.2014.07.002. Murphy, D. J. (2005). Comprehensive non-clinical respiratory evaluation of promising new drugs. Toxicology and Applied Pharmacology, 207, 414–424. Murphy, D. J. (2013). Respiratory safety pharmacology—Current practice and future directions. Regulatory Toxicology and Pharmacology, 69, 135–140. Murphy, D. J. (2014). Optimizing the use of methods and measurement endpoints in respiratory safety pharmacology. Journal of Pharmacological and Toxicological Methods. http://dx.doi.org/10.1016/j.vascn.2014.03.174. O'Hara, T., Virág, L., Varró, A., & Rudy, Y. (2011). Simulation of the undiseased human cardiac ventricular action potential: Model formulation and experimental validation. PLoS Computational Biology, 7(5), e1002061. http://dx.doi.org/10.1371/journal.pcbi. 1002061. Peng, S., Lacerda, A. E., Kirsch, G. E., Brown, A. M., & Bruening-Wright, A. (2010). The action potential and comparative pharmacology of stem cell-derived human cardiomyocytes. Journal of Pharmacological and Toxicological Methods, 61, 277–286.

P

466 467 468 469 470 471 472 473 474 475 476 477 Q15 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498

5

U

N C O

R

R

E

C

T

E

D

530

Please cite this article as: Pugsley, M.K., et al., Safety pharmacology in 2014: New focus on non-cardiac methods and models, Journal of Pharmacological and Toxicological Methods (2014), http://dx.doi.org/10.1016/j.vascn.2014.08.004

499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529

Safety pharmacology in 2014: new focus on non-cardiac methods and models.

"What do you know about Safety Pharmacology?" This is the question that was asked in 2000 with the inception of the Safety Pharmacology Society (SPS)...
288KB Sizes 2 Downloads 7 Views