- Email: [email protected]
CNS safety of spadin
Abstracts
0132 Characterization of canine models of heart failure with reduced and preserved ejection fraction Brad Youngblooda, Carlos del Rioa, Kevin Rendera, Beth Geista, Yukie Ueyamaa, Jeff Wallerya, Robert Hamlina,b a
QTest Labs, Columbus, OH, USA The Ohio State University, Columbus, OH, USA
375
was devoid of effects on sleep wake cycle up to 1 mg/kg (IV). Moreover, it caused no change in EEG rhythm power whatever the sleep/wake cycle. Likewise, spadin had no effect on short and long term memory up to 1 mg/kg (IP). All other CNS stimulant agents caused sleep disturbances and/or decreased short term memory ability. These results suggest that spadin could have a safe profile when compared to antidepressant drugs and does not behave as classical stimulant agents.
b
Pharmaceutical agents are often tested in animals with normal physiology; however, they are destined to be used by patients with altered physiology and disease states. This study aimed to evaluate the physiologic changes seen in the development of heart failure in a beagle dog following tachypacing (reduced EF; HFrEF) or renal– prival hypertension (preserved EF; HFpEF). In short, beagle dogs were instrumented via thoracotomy for analysis of left ventricular pressure and volume/dimensions. A subset of animals also had either right ventricular endovascular or epicardial pacing leads to induce HFrEF via tachypacing. Another subset of animals underwent bilateral modified Page renal wrapping to induce chronic hypertension and diastolic dysfunction with preserved ejection fraction (HFpEF). Both models resulted in the development of different phenotypic changes. Control values were calculated in a subset of animals prior to induction of heart failure (EF: 64 ± 1%, LVEDP: 9 ± 0 mmHg, LVESP: 119 ± 4 mmHg, PRSW: 82 ± 3 mmHg, EDV: 31 ± 1 mL). HFrEF resulted in changes consistent with decreased contractile state and ventricular dilation (EF: 39 ± 1%, LVEDP: 22 ± 1 mmHg, LVESP: 110 ± 3 mmHg, PRSW: 52 ± 1 mmHg, EDV: 51 ± 1 mL). HFpEF resulted in changes associated with chronic hypertension (EF: 61 ± 1%, LVESP: 145 ± 1 mmHg, PRSW: 81 ± 2 mmHg, EDV: 26 ± 0 mL) and elevated filling pressures (LVEDP: 20 ± 1 mmHg). Given the differences in phenotype, the choice of an appropriate model is paramount for analysis of pharmaceutical agents prior to inhuman testing. doi:10.1016/j.vascn.2016.02.131
0133 CNS safety of spadin Pascal Champerouxa, Vincent Maleyssona, Emmanuel Bracqa, Anne Maurina, Jean Mazellab, Catherine Heurteauxb, Marc Borsottob, Serge Richarda a
CERB, Baugy, France IPMC, Nice, France
b
Spadin is a Sortilin-derived peptide targeting TREK-1 channels potentially active in depression with an immediate onset of action. In this work, we studied its CNS safety profile in comparison with antidepressant drugs (imipramine, desipramine) and other CNS stimulant agents (caffeine, amphetamine, cocaine, tramadol). Since most deleterious adverse effects expected with CNS stimulant agents are sleep and memory disturbances, we focused our investigations on these two possible side effects. Effects on sleep/wake cycles of spadin were studied by telemetry in rats at single doses of 0.1 and 1 mg/kg by the intravenous route (×10 and × 100 the pharmacological effective dose by the IV route). Effects on EEG rhythms power in each wake/sleep state (active, quiet wake, slow waves sleep and REM) were also analyzed. Effects on spatial learning and memory processes were assessed in the radial arm water maze (RAWM) at single doses of 0.1 and 1 mg/kg by the peritoneal route (×1 and × 10 the pharmacological effective dose by the peritoneal route). Spadin
doi:10.1016/j.vascn.2016.02.132
0134 The predictive value of the rodent neurofunctional assessment for commonly reported adverse events in phase I clinical trials Andrew Meadb,j, Hamid Amouzadehc, Kathryn Chapmana, Lorna Ewartd, Alessandra Giarolae, Samuel Jacksona, Philip Jarvisf, Pierre Jordaanf, Will Redferng, Martin Traeberth, Jean-Pierre Valenting,i, Hugo Vargasc a
National Centre for the Replacement, Refinement and Reduction of Animals in Research, London, UK b Pfizer, Groton, CT, USA c Amgen Inc, Thousand Oaks, CA, USA d AstraZeneca, Mölndal, Sweden e GlaxoSmithKline, Ware, UK f Novartis, Basel, Switzerland g AstraZeneca, Macclesfield, UK h Novartis Institutes of Biomedical Research, Basel, Switzerland i UCB, Braine l’Alleud, Belgium j AstraZeneca, Cambridge, UK Central Nervous System (CNS)-related safety concerns detected nonclinically and clinically are major contributors to delays and failure during the development of new drugs. Translational safety assessment could improve the probability of success for new drugs through a critical evaluation of safety decision making. In this analysis, the shared CNS-related safety data of 141 small molecules from five pharmaceutical companies derived from rodent neurofunctional assessments was investigated to identify the concordance between nonclinical neurofunctional assessments and the most common adverse events (AEs) in phase I First In Human (FIH) trials. The data indicate that, in the context of this analysis, the rodent neurofunctional assessment did not detect or predict the most commonly reported AEs in the FIH study, which were headache, nausea, dizziness, fatigue/somnolence and pain. Furthermore, the presence of any finding in the same nonclinical assessment does not predict the likelihood of compounds producing any of these commonly reported AEs during the FIH study. This analysis indicates that the findings from the rodent neurofunctional assessment cannot be used to predict the presence of commonly observed AEs in FIH studies. However, it should be emphasized that those AEs with the highest prevalence in FIH studies (i.e. those that occurred in the greatest proportion of clinical studies) were often not responsible for delaying or stopping further progression of candidate drugs. Additional more serious AEs that might stop drug development occurred at an incidence rate in our clinical dataset which was too low to enable meaningful statistical analysis of nonclinical to clinical translation.
doi:10.1016/j.vascn.2016.02.133
0132 Characterization of canine models of heart failure with reduced and preserved ejection fraction Brad Youngblooda, Carlos del Rioa, Kevin Rendera, Beth Geista, Yukie Ueyamaa, Jeff Wallerya, Robert Hamlina,b a
QTest Labs, Columbus, OH, USA The Ohio State University, Columbus, OH, USA
375
was devoid of effects on sleep wake cycle up to 1 mg/kg (IV). Moreover, it caused no change in EEG rhythm power whatever the sleep/wake cycle. Likewise, spadin had no effect on short and long term memory up to 1 mg/kg (IP). All other CNS stimulant agents caused sleep disturbances and/or decreased short term memory ability. These results suggest that spadin could have a safe profile when compared to antidepressant drugs and does not behave as classical stimulant agents.
b
Pharmaceutical agents are often tested in animals with normal physiology; however, they are destined to be used by patients with altered physiology and disease states. This study aimed to evaluate the physiologic changes seen in the development of heart failure in a beagle dog following tachypacing (reduced EF; HFrEF) or renal– prival hypertension (preserved EF; HFpEF). In short, beagle dogs were instrumented via thoracotomy for analysis of left ventricular pressure and volume/dimensions. A subset of animals also had either right ventricular endovascular or epicardial pacing leads to induce HFrEF via tachypacing. Another subset of animals underwent bilateral modified Page renal wrapping to induce chronic hypertension and diastolic dysfunction with preserved ejection fraction (HFpEF). Both models resulted in the development of different phenotypic changes. Control values were calculated in a subset of animals prior to induction of heart failure (EF: 64 ± 1%, LVEDP: 9 ± 0 mmHg, LVESP: 119 ± 4 mmHg, PRSW: 82 ± 3 mmHg, EDV: 31 ± 1 mL). HFrEF resulted in changes consistent with decreased contractile state and ventricular dilation (EF: 39 ± 1%, LVEDP: 22 ± 1 mmHg, LVESP: 110 ± 3 mmHg, PRSW: 52 ± 1 mmHg, EDV: 51 ± 1 mL). HFpEF resulted in changes associated with chronic hypertension (EF: 61 ± 1%, LVESP: 145 ± 1 mmHg, PRSW: 81 ± 2 mmHg, EDV: 26 ± 0 mL) and elevated filling pressures (LVEDP: 20 ± 1 mmHg). Given the differences in phenotype, the choice of an appropriate model is paramount for analysis of pharmaceutical agents prior to inhuman testing. doi:10.1016/j.vascn.2016.02.131
0133 CNS safety of spadin Pascal Champerouxa, Vincent Maleyssona, Emmanuel Bracqa, Anne Maurina, Jean Mazellab, Catherine Heurteauxb, Marc Borsottob, Serge Richarda a
CERB, Baugy, France IPMC, Nice, France
b
Spadin is a Sortilin-derived peptide targeting TREK-1 channels potentially active in depression with an immediate onset of action. In this work, we studied its CNS safety profile in comparison with antidepressant drugs (imipramine, desipramine) and other CNS stimulant agents (caffeine, amphetamine, cocaine, tramadol). Since most deleterious adverse effects expected with CNS stimulant agents are sleep and memory disturbances, we focused our investigations on these two possible side effects. Effects on sleep/wake cycles of spadin were studied by telemetry in rats at single doses of 0.1 and 1 mg/kg by the intravenous route (×10 and × 100 the pharmacological effective dose by the IV route). Effects on EEG rhythms power in each wake/sleep state (active, quiet wake, slow waves sleep and REM) were also analyzed. Effects on spatial learning and memory processes were assessed in the radial arm water maze (RAWM) at single doses of 0.1 and 1 mg/kg by the peritoneal route (×1 and × 10 the pharmacological effective dose by the peritoneal route). Spadin
doi:10.1016/j.vascn.2016.02.132
0134 The predictive value of the rodent neurofunctional assessment for commonly reported adverse events in phase I clinical trials Andrew Meadb,j, Hamid Amouzadehc, Kathryn Chapmana, Lorna Ewartd, Alessandra Giarolae, Samuel Jacksona, Philip Jarvisf, Pierre Jordaanf, Will Redferng, Martin Traeberth, Jean-Pierre Valenting,i, Hugo Vargasc a
National Centre for the Replacement, Refinement and Reduction of Animals in Research, London, UK b Pfizer, Groton, CT, USA c Amgen Inc, Thousand Oaks, CA, USA d AstraZeneca, Mölndal, Sweden e GlaxoSmithKline, Ware, UK f Novartis, Basel, Switzerland g AstraZeneca, Macclesfield, UK h Novartis Institutes of Biomedical Research, Basel, Switzerland i UCB, Braine l’Alleud, Belgium j AstraZeneca, Cambridge, UK Central Nervous System (CNS)-related safety concerns detected nonclinically and clinically are major contributors to delays and failure during the development of new drugs. Translational safety assessment could improve the probability of success for new drugs through a critical evaluation of safety decision making. In this analysis, the shared CNS-related safety data of 141 small molecules from five pharmaceutical companies derived from rodent neurofunctional assessments was investigated to identify the concordance between nonclinical neurofunctional assessments and the most common adverse events (AEs) in phase I First In Human (FIH) trials. The data indicate that, in the context of this analysis, the rodent neurofunctional assessment did not detect or predict the most commonly reported AEs in the FIH study, which were headache, nausea, dizziness, fatigue/somnolence and pain. Furthermore, the presence of any finding in the same nonclinical assessment does not predict the likelihood of compounds producing any of these commonly reported AEs during the FIH study. This analysis indicates that the findings from the rodent neurofunctional assessment cannot be used to predict the presence of commonly observed AEs in FIH studies. However, it should be emphasized that those AEs with the highest prevalence in FIH studies (i.e. those that occurred in the greatest proportion of clinical studies) were often not responsible for delaying or stopping further progression of candidate drugs. Additional more serious AEs that might stop drug development occurred at an incidence rate in our clinical dataset which was too low to enable meaningful statistical analysis of nonclinical to clinical translation.
doi:10.1016/j.vascn.2016.02.133