CiToxLAB North America

Laval, Canada

CiToxLAB North America

Laval, Canada
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Authier S.,CIToxLAB North America | Vargas H.M.,Amgen | Curtis M.J.,St Thomas Hospital | Holbrook M.,Covance | Pugsley M.K.,Drug Safety science
Journal of Pharmacological and Toxicological Methods | Year: 2013

Introduction: The Safety Pharmacology (SP) Society (SPS) conducted an industry survey in 2012 in an attempt to define current industry practices as they relate to inclusion of safety pharmacology (SP) endpoints into Toxicology studies. Methods: A total of 361 participants from Asia (9.1%), Europe (19.4%) and North America (71.4%) responded to the survey. The preponderance of respondents were toxicologists (53.2%) followed by safety pharmacologists (27.2%) and scientists involved in the conduct of both disciplines (19.6%). Most participants (58.6%) were from pharmaceutical companies employing more than 500 employees. Results: A majority (68.2%) reported having experience in designing, performing or interpreting the SP component of a study when performed as part of a toxicology study. Some participants (42.0%) had submitted data to a regulatory agency where ICHS7 studies were performed as part of a toxicology study rather than as a standalone study. When comparing species that were used in studies in which SP was added to toxicology studies, canines were the most frequently reported animals used for new chemical entities (NCE) whereas non-human (NH) primates were the most frequent for the assessment of biological agents. The most frequent primary motivator for adding ICHS7 SP endpoints to regulatory toxicology studies was to generate additional data to allow for determination of an integrated risk assessment thereby testing Confidence in Safety (CIS) to better manage and/or mitigate risk. The current ability to add safety pharmacology endpoints into regulatory toxicology studies was used to address a specific concern (by 42.1% of respondents) to allow management of risk more effectively (36.8%) or to generate data that contributes to cessation of the progression of a compound (21.1%). For an NCE, SP measurements in toxicology studies were conducted in addition to standalone SP studies (by 40.6% of respondents) or in addition/instead of standalone safety pharmacology studies (by 39.8% of respondents). For biological agents, a majority (74.3%) indicated SP measurements in toxicology were conducted instead of standalone studies as outlined in the ICHS6 guideline while inclusion of SP endpoints in toxicology studies for biological agents in addition to standalone studies was reported by only 25.7% of the respondents. Discussion: The survey highlights that obtaining regulatory agreement for the proposed combined SP/Tox study designs may be useful before study conduct in some cases. Respondents suggest that such discussion could occur at the pre-IND meeting before the IND/CTA enabling program. © 2013 Elsevier Inc.

Authier S.,CiToxLAB North America | Delatte M.S.,U.S. Food and Drug Administration | Kallman M.-J.,Kallman Preclinical Consulting | Stevens J.,Merck And Co. | Markgraf C.,Merck And Co.
Journal of Pharmacological and Toxicological Methods | Year: 2016

Electroencephalogram (EEG) data in nonclinical species can play a critical role in the successful evaluation of a compound during drug development, particularly in the evaluation of seizure potential and for monitoring changes in sleep. Yet, while non-invasive electrocardiogram (ECG) monitoring is commonly included in preclinical safety studies, pre-dose or post-dose EEG assessments are not. Industry practices as they relate to preclinical seizure liability and sleep assessments are not well characterized and the extent of preclinical EEG testing varies between organizations. In the current paper, we discuss the various aspects of preclinical EEG to characterize drug-induced seizure risk and sleep disturbances, as well as describe the use of these data in a regulatory context. An overview of EEG technology—its correct application and its limitations, as well as best practices for setting up the animal models is presented. Sleep and seizure detection are discussed in detail. A regulatory perspective on the use of EEG data is provided and, tying together the previous topics is a discussion of the translational aspects of EEG. © 2016 The Authors

Pannkuk E.L.,Georgetown University | Laiakis E.C.,Georgetown University | Authier S.,CiToxLAB North America | Wong K.,CiToxLAB North America | Fornace A.J.,Georgetown University
Journal of Proteome Research | Year: 2017

Ionizing radiation (IR) directly damages cells and tissues or indirectly damages them through reactive free radicals that may lead to longer term adverse sequelae such as cancers, persistent inflammation, or possible death. Potential exposures include nuclear reactor accidents, improper disposal of equipment containing radioactive materials or medical errors, and terrorist attacks. Metabolomics (comprehensive analysis of compounds <1 kDa) by mass spectrometry (MS) has been proposed as a tool for high-throughput biodosimetry and rapid assessment of exposed dose and triage needed. While multiple studies have been dedicated to radiation biomarker discovery, many have utilized liquid chromatography (LC) MS platforms that may not detect particular compounds (e.g., small carboxylic acids or isomers) that complementary analytical tools, such as gas chromatography (GC) time-of-flight (TOF) MS, are ideal for. The current study uses global GC-TOF-MS metabolomics to complement previous LC-MS analyses on nonhuman primate biofluids (urine and serum) 7 days after exposure to 2, 4, 6, 7, and 10 Gy IR. Multivariate data analysis was used to visualize differences between control and IR exposed groups. Univariate analysis was used to determine a combined 26 biomarkers in urine and serum that significantly changed after exposure to IR. We found several metabolites involved in tricarboxylic acid cycle function, amino acid metabolism, and host microbiota that were not previously detected by global and targeted LC-MS studies. © 2017 American Chemical Society.

Rachalski A.,University of Montréal | Authier S.,CiToxLAB North America | Bassett L.,CiToxLAB North America | Pouliot M.,CiToxLAB North America | Mongrain V.,University of Montréal
Journal of Sleep Research | Year: 2014

Cynomolgus monkeys are widely used as models of diseases and in pre-clinical studies to assess the impact of new pharmacotherapies on brain function and behaviour. However, the time course of electroencephalographic delta activity during sleep, which represents the main marker of sleep intensity associated with recovery during sleep, has never been described in this non-human primate. In this study, telemetry implants were used to record one spontaneous 24-h sleep-wake cycle in four freely-moving Cynomolgus monkeys, and to quantify the time course of electroencephalographic activity during sleep using spectral analysis. Animals presented a diurnal activity pattern interrupted by short naps. During the dark period, most of the time was spent in sleep with non-rapid eye movement sleep/rapid eye movement sleep alternations and sleep consolidation profiles intermediate between rodents and humans. Deep non-rapid eye movement sleep showed a typical predominance at the beginning of the night with decreased propensity in the course of the night, which was accompanied by a progressive increase in rapid eye movement sleep duration. Spectral profiles showed characteristic changes between vigilance states as reported in other mammalian species. Importantly, delta activity also followed the expected time course of variation, showing a build-up with wakefulness duration and dissipation across the night. Thus, Cynomolgus monkeys present typical characteristics of sleep architecture and spectral structure as those observed in other mammalian species including humans, validating the use of telemetry in this non-human primate model for translational sleep studies. © 2014 European Sleep Research Society.

PubMed | U.S. Food and Drug Administration, UCB Pharma, Amgen, Kallman Preclinical Consulting and 7 more.
Type: | Journal: Journal of pharmacological and toxicological methods | Year: 2016

The Safety Pharmacology Society (SPS) conducted an industry survey in 2015 to identify industry practices as they relate to central, peripheral and autonomic nervous system (CNS) drug safety testing. One hundred fifty-eight (158) participants from Asia (16%), Europe (20%) and North America (56%) responded to the survey. 52% of participants were from pharmaceutical companies (>1000 employees). Oncology (67%) and neurology/psychiatry (66%) were the most frequent target indications pursued by companies followed by inflammation (48%), cardiovascular (43%), metabolic (39%), infectious (37%), orphan (32%) and respiratory (29%) diseases. Seizures (67% of participants), gait abnormalities (67%), tremors (65%), emesis (56%), sedation (52%) and salivation (47%) were the most commonly encountered CNS issues in pre-clinical drug development while headache (65%), emesis/nausea (60%), fatigue (51%) and dizziness (49%) were the most frequent issues encountered in Phase I clinical trials. 54% of respondents reported that a standard battery of tests applied to screen drug candidates was the approach most commonly used to address non-clinical CNS safety testing. A minority (14% of all participants) reported using electroencephalography (EEG) screening prior to animal inclusion on toxicology studies. The most frequent group size was n=8 for functional observation battery (FOB), polysomnography and seizure liability studies. FOB evaluations were conducted in a dedicated room (78%) by blinded personnel (66%) with control for circadian cycle (55%) effects (e.g., dosing at a standardized time; balancing time of day across treatment groups). The rat was reported as the most common species used for seizure liability, nerve conduction and drug-abuse liability testing.

Authier S.,CiToxLAB North America | Pugsley M.K.,Janssen Pharmaceutical | Curtis M.J.,Rayne Institute
Handbook of Experimental Pharmacology | Year: 2015

Evaluation of the effects of a drug on arterial blood pressure is important in nonclinical safety pharmacology assessment. Detecting large and obvious changes in blood pressure is an unchallenging task. Detecting small changes is more difficult, and interpretation of findings requires careful risk/benefit evaluation. Detecting subtle and small changes in blood pressure is important in particular with respect to increases, since blood pressure above the normal range is associated with increased risk of stroke and sudden cardiac death. Cardiovascular safety pharmacology has been preoccupied with drug-induced changes in the electrocardiogram, and by comparison, there has been little in the way of contemporaneous improvements in the level of complexity and sophistication involved in blood pressure assessment. Thus, it is important to understand the nature of drug-induced changes in blood pressure, appreciate the plethora of agents currently used clinically (and over the counter) that alter blood pressure and understand safety pharmacology study design in order to optimize assessment of a new chemical entity (NCE) or biologic agent in this context. © Springer-Verlag Berlin Heidelberg 2015.

Bassett L.,CIToxLAB North America | Troncy E.,University of Montréal | Robichaud A.,SCIREQ Scientific Respiratory Equipment Inc. | Schuessler T.F.,SCIREQ Scientific Respiratory Equipment Inc. | And 5 more authors.
Journal of Pharmacological and Toxicological Methods | Year: 2014

Introduction: A number of drugs in clinical trials are discontinued due to potentially life-threatening airway obstruction. As some drugs may not cause changes in core battery parameters such as tidal volume (Vt), respiratory rate (RR) or minute ventilation (MV), including measurements of respiratory mechanics in safety pharmacology studies represents an opportunity for design refinement. The present study aimed to test a novel non-invasive methodology to concomitantly measure respiratory system resistance (Rrs) and conventional respiratory parameters (Vt, RR, MV) in conscious Beagle dogs and cynomolgus monkeys. Methods: An Airwave Oscillometry system (tremoFlo; THORASYS Inc., Montreal, Canada) was used to concomitantly assess Rrs and conventional respiratory parameters before and after intravenous treatment with a bronchoactive agent. Respiratory mechanics measurements were performed by applying a short (i.e. 16s) single high frequency (19Hz) waveform at the subject's airway opening via a face mask. During measurements, pressure and flow signals were recorded. After collection of baseline measurements, methacholine was administered intravenously to Beagle dogs (n=6) and cynomolgus monkeys (n=4) at 8 and 68μg/kg, respectively. Results: In dogs, methacholine induced significant increases in Vt, RR and MV while in monkeys, it only augmented RR. A significant increase in Rrs was observed after methacholine administration in both species with mean percentage peak increases from baseline of 88 (53)% for dogs and 28 (16)% for cynomolgus monkeys. Conclusion: Airwave Oscillometry appears to be a promising non-invasive methodology to enable respiratory mechanics measurements in conscious large animals, a valuable refinement in respiratory safety pharmacology. © 2014 Elsevier Inc.

Bassett L.,CIToxLAB North America | Bassett L.,University of Montréal | Troncy E.,University of Montréal | Pouliot M.,CIToxLAB North America | And 4 more authors.
Journal of Pharmacological and Toxicological Methods | Year: 2014

Introduction: Non-clinical seizure liability studies typically aim to: 1) confirm the nature of EEG activity during abnormal clinical signs, 2) identify premonitory clinical signs, 3) measure plasma levels at seizure onset, 4) demonstrate that drug-induced seizures are self-limiting, 5) confirm that conventional drugs (e.g. diazepam) can treat drug-induced seizures and 6) confirm the no observed adverse effect level (NOAEL) at EEG. Our aim was to originally characterize several of these items in a three species comparative study. Methods: Cynomolgus monkey, Beagle dog and Sprague-Dawley rat with EEG telemetry transmitters were used to obtain EEG using the 10-20 system. Pentylenetetrazol (PTZ) was used to determine seizure threshold or as a positive seizurogenic agent. Clinical signs were recorded and premonitory signs were evaluated. In complement, other pharmacological agents were used to illustrate various safety testing strategies. Results: Intravenous PTZ doses required to induce clonic convulsions were 36.1 (3.8), 56.1 (12.7) and 49.4 (11.7) mg/kg, in Beagle dogs, cynomolgus monkeys and Sprague-Dawley rats, respectively. Premonitory clinical signs typically included decreased physical activity, enhanced physiological tremors, hypersalivation, ataxia, emesis (except in rats) and myoclonus. In Sprague-Dawley rats, amphetamine (PO) increased high (approximately 40-120. Hz), and decreased low (1-14. Hz) frequencies. In cynomolgus monkeys, caffeine (IM) increased power in high (14-127. Hz), and attenuated power in low (1-13. Hz) frequencies. In the rat PTZ infusion seizure threshold model, yohimbine (SC and IV) and phenobarbital (IP) confirmed to be reliable positive controls as pro- and anticonvulsants, respectively. Discussion: Telemetry video-EEG for seizure liability investigations was characterized in three species. Rats represent a first-line model in seizure liability assessments. Beagle dogs are often associated with overt susceptibility to seizure and are typically used in seizure liability studies only if required by regulators. Non-human primates represent an important model in seizure liability assessments given similarities to humans and a high translational potential. © 2014 The Authors.

Pannkuk E.L.,Georgetown University | Laiakis E.C.,Georgetown University | Authier S.,CiToxLAB North America | Wong K.,CiToxLAB North America | And 2 more authors.
Radiation Research | Year: 2015

Due to concerns surrounding potential large-scale radiological events, there is a need to determine robust radiation signatures for the rapid identification of exposed individuals, which can then be used to guide the development of compact field deployable instruments to assess individual dose. Metabolomics provides a technology to process easily accessible biofluids and determine rigorous quantitative radiation biomarkers with mass spectrometry (MS) platforms. While multiple studies have utilized murine models to determine radiation biomarkers, limited studies have profiled nonhuman primate (NHP) metabolic radiation signatures. In addition, these studies have concentrated on short-term biomarkers (i.e., <72 h). The current study addresses the need for biomarkers beyond 72 h using a NHP model. Urine samples were collected at 7 days postirradiation (2, 4, 6, 7 and 10 Gy) and processed with ultra-performance liquid chromatography (UPLC) quadrupole time-of-flight (QTOF) MS, acquiring global metabolomic radiation signatures. Multivariate data analysis revealed clear separation between control and irradiated groups. Thirteen biomarkers exhibiting a dose response were validated with tandem MS. There was significantly higher excretion of l-carnitine, l-acetylcarnitine, xanthine and xanthosine in males versus females. Metabolites validated in this study suggest perturbation of several pathways including fatty acid β oxidation, tryptophan metabolism, purine catabolism, taurine metabolism and steroid hormone biosynthesis. In this novel study we detected long-term biomarkers in a NHP model after exposure to radiation and demonstrate differences between sexes using UPLC-QTOF-MS-based metabolomics technology. © 2015 by Radiation Research Society.

PubMed | CiToxLAB North America and University of Montréal
Type: | Journal: Journal of pharmacological and toxicological methods | Year: 2016

Cardiovascular effects are considered frequent during drug safety testing. This investigation aimed to characterize the pharmacological response of the conscious telemetered rat in vivo model to known cardiovascular active agents. These effects were analyzed using statistical analysis and cloud representation with marginal distribution curves for the contractility index and heart rate as to assess the effect relationship between cardiac variables. Arterial blood pressure, left ventricular pressure, electrocardiogram and body temperature were monitored. The application of data cloud with marginal distribution curves to heart rate and contractility index provided an interesting tactic during the interpretation of drug-induced changes particularly during selective time resolution (i.e. marginal distribution curves restricted to Tmax). Taken together, the present data suggests that marginal distribution curves can be a valuable interpretation strategy when using the rat cardiovascular telemetry model to detect drug-induced cardiovascular effects. Marginal distribution curves could also be considered during the interpretation of other inter-dependent parameters in safety pharmacology studies.

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