Adaptation of safety pharmacology cardiovascular and respiratory methodology for use on juvenile...
1
Impedance is a recognized methodology for respiratory measure- ment; however the use of impedance respiratory monitoring in freely moving cynomolgus monkeys has not yet been reported. This study explored impedance respiratory monitoring as a novel implantable telemetry monitoring strategy. A surgically implanted telemetry transmitter with ECG (DII), arterial pressure, physical activity, body temperature, respiratory rate and tidal volume (TV) was character- ized. A longitudinal incision was performed lateral to the linea alba. The internal abdominal oblique muscle was separated from the aponeurosis of the transverses abdominis by blunt dissection. A transmitter was inserted between the internal abdominal oblique muscle and the aponeurosis of the transverses abdominis. Impedance electrodes were placed subcutaneously on the lateral aspect of the thorax. After recovery, controlled tidal volumes (20, 40 and 60 mL) were used in 6 anesthetized cynomolgus females to evaluate the effects of body positions on respiratory measurements. All correla- tions were above 98%. Animals were followed over time to assess both accuracy and stability of telemetric impedance measurements. Slight changes in the impedance signal were noted between the surgery and two weeks post-implant. Impedance remained stable over the following 2-month monitoring period. Circadian rhythms of respiratory rate and TV were correlated with cardiovascular parameters. In conclusion, this new telemetry monitoring modality could be valuable in pharmacological investigations when the use of cynomolgus monkeys is justified. doi:10.1016/j.vascn.2010.11.015 Poster Number: 12 Board Number: 12 Translational medicine: Can we use publicly available data in correlating preclinical with clinical studies? Ard Teisman a , Pieter-Jan Guns b , Karel Van Ammel a , Rob Towart a , Nenad Sarapa c , David Gallacher a a Johnson & Johnson EDC, Beerse, Belgium b Formerly Johnson & Johnson EDC, Beerse, Belgium and University of Antwerp, Antwerp, Belgium c Formerly Johnson & Johnson Clinical East Coast, Raritan, NJ, United States Criticism of preclinical models is based on their apparent lack of reliability to predict clinical events. In the cardiovascular (CV) safety area blockade of the IKr channel can lead to QT prolongation, which in turn may lead to TdP. Although we know that drug-induced TdP may be caused by block of IKr, we also know that some IKr blockers do not necessarily induce QT-prolongation/TdP. To answer the question “how good are current preclinical models?” one needs to review both preclinical and clinical data in a wide range of chemical and pharmacological classes. The majority of clinical data is not in the public domain. Within this project we compared both J&J internal and publicly available clinical CVdata with results of preclinical models. We evaluated several different clinical data sources and identified 80 clinical reports on 73 compounds with different levels of CV data. The data were collected in a data warehouse and compared with preclinical data. Due to the different levels of detail and large variability of designs etc., the actual number of compounds that could be used was significantly reduced. Preliminary analysis shows that TQT-data tend to have the lowest variability, and that these should preferably be used for comparison with preclinical ECG-models. Unfortunately, little of this high quality data is available in the public domain, as many compounds will not reach the clinical stage. Using suboptimal clinical data diminishes the reputation of preclinical models. Cross company collaboration and improved Phase I study designs may improve this situation. doi:10.1016/j.vascn.2010.11.016 Poster Number: 13 Board Number: 13 Adaptation of safety pharmacology cardiovascular and respiratory methodology for use on juvenile toxicity studies Kevin Norton, Keith Robinson, Mark Vezina Charles River Laboratories, Senneville, Quebec, Canada The EMEA Guideline on the need for nonclinical testing in juvenile animals on human pharmaceuticals for pediatric indications and FDA Guidance Document. Nonclinical safety evaluation of pediatric drug products; require the conduct of juvenile toxicity studies intended to bridge the developmental toxicity studies adult toxicity studies. As per the EMEA guidance document, the objective of such studies is to assess “potentially different safety profiles from those seen in adults.” With new chemical entities being specifically evaluated to assess effects on overall growth of the organ systems that develop postnatally (e.g., skeletal, renal, lung, neurological, immunologic and reproductive systems). We have looked at incorporation of traditional assessments of safety pharmacology core battery assessments for CNS, respiratory and cardiovascular studies in juvenile toxicity studies. We demonstrate the use of a modified functional observation battery and whole body plethysmography to assess effects on CNS and respiratory parameters, respectively, in rats between day 10 and sexual maturation (approximately day 50). Whilst beagle dogs approximately 3 to 4 month of age were instrumented with DSI telemetry transmitters to assess cardiovascular effect. The data reported illustrate that traditional safety pharmacol- ogy can be adapted to meet the growing requirements for juvenile toxicity studies. doi:10.1016/j.vascn.2010.11.017 Poster Number: 14 Board Number: 14 Measurement of bronchoconstriction in conscious rats: Elegant technique, elusive recordings Lorna C. Ewart a , Katherine Elliott b , Michael Haley b , Tom Holland b , Sally-Ann Ricketts c , Alan McCarthy b , Lisa Williams b , Jean-Pierre Valentin b a AstraZeneca, Macclesfield, Cheshire, United Kingdom b Safety Assessment, AstraZeneca, Macclesfield, Cheshire, United Kingdom c DECS, AstraZeneca, Macclesfield, Cheshire, United Kingdom Placement of a pressure-sensitive catheter radio-telemetry device, beneath the pleural surface, enables assessment of bronchoconstric- tion in parallel with changes in rate and depth of breathing (Murphy et al. 1998). Here, we assess this approach using an infusion of methacholine (MCh) up to 30 μg/kg/min or vehicle (saline) via the tail vein in adapted head-out plethysmography (HOP) chambers. Resistance measured by the telemetric method in conscious male rats (18 Han Wistar, 10 Sprague Dawley) was compared to resistance Abstracts e5
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Transcript of Adaptation of safety pharmacology cardiovascular and respiratory methodology for use on juvenile...
Impedance is a recognized methodology for respiratory measure-ment; however the use of impedance respiratory monitoring in freelymoving cynomolgus monkeys has not yet been reported. This studyexplored impedance respiratory monitoring as a novel implantabletelemetry monitoring strategy. A surgically implanted telemetrytransmitter with ECG (DII), arterial pressure, physical activity, bodytemperature, respiratory rate and tidal volume (TV) was character-ized. A longitudinal incision was performed lateral to the linea alba.The internal abdominal oblique muscle was separated from theaponeurosis of the transverses abdominis by blunt dissection. Atransmitter was inserted between the internal abdominal obliquemuscle and the aponeurosis of the transverses abdominis. Impedanceelectrodes were placed subcutaneously on the lateral aspect of thethorax. After recovery, controlled tidal volumes (20, 40 and 60 mL)were used in 6 anesthetized cynomolgus females to evaluate theeffects of body positions on respiratory measurements. All correla-tions were above 98%. Animals were followed over time to assessboth accuracy and stability of telemetric impedance measurements.Slight changes in the impedance signal were noted between thesurgery and two weeks post-implant. Impedance remained stableover the following 2-month monitoring period. Circadian rhythmsof respiratory rate and TV were correlated with cardiovascularparameters. In conclusion, this new telemetry monitoring modalitycould be valuable in pharmacological investigations when the useof cynomolgus monkeys is justified.
doi:10.1016/j.vascn.2010.11.015
Poster Number: 12Board Number: 12
Translational medicine: Can we use publicly available datain correlating preclinical with clinical studies?Ard Teismana, Pieter-Jan Gunsb, Karel Van Ammela, Rob Towarta,Nenad Sarapac, David Gallachera
aJohnson & Johnson EDC, Beerse, BelgiumbFormerly Johnson & Johnson EDC, Beerse, Belgium and University ofAntwerp, Antwerp, BelgiumcFormerly Johnson & Johnson Clinical East Coast, Raritan, NJ,United States
Criticism of preclinical models is based on their apparent lack ofreliability to predict clinical events. In the cardiovascular (CV) safetyarea blockade of the IKr channel can lead to QT prolongation, whichin turn may lead to TdP. Although we know that drug-induced TdPmay be caused by block of IKr, we also know that some IKr blockersdo not necessarily induce QT-prolongation/TdP. To answer thequestion “how good are current preclinical models?” one needs toreview both preclinical and clinical data in a wide range of chemicaland pharmacological classes. The majority of clinical data is not in thepublic domain. Within this project we compared both J&J internal andpublicly available clinical CVdata with results of preclinical models.We evaluated several different clinical data sources and identified80 clinical reports on 73 compounds with different levels of CV data.The data were collected in a data warehouse and compared withpreclinical data. Due to the different levels of detail and largevariability of designs etc., the actual number of compounds that couldbe used was significantly reduced. Preliminary analysis shows thatTQT-data tend to have the lowest variability, and that these shouldpreferably be used for comparison with preclinical ECG-models.Unfortunately, little of this high quality data is available in the publicdomain, as many compounds will not reach the clinical stage. Using
suboptimal clinical data diminishes the reputation of preclinicalmodels. Cross company collaboration and improved Phase I studydesigns may improve this situation.
doi:10.1016/j.vascn.2010.11.016
Poster Number: 13Board Number: 13
Adaptation of safety pharmacology cardiovascular and respiratorymethodology for use on juvenile toxicity studiesKevin Norton, Keith Robinson, Mark Vezina
Charles River Laboratories, Senneville, Quebec, Canada
The EMEA Guideline on the need for nonclinical testing in juvenileanimals on human pharmaceuticals for pediatric indications andFDA Guidance Document. Nonclinical safety evaluation of pediatricdrug products; require the conduct of juvenile toxicity studiesintended to bridge the developmental toxicity studies adult toxicitystudies. As per the EMEA guidance document, the objective ofsuch studies is to assess “potentially different safety profiles fromthose seen in adults.” With new chemical entities being specificallyevaluated to assess effects on overall growth of the organ systemsthat develop postnatally (e.g., skeletal, renal, lung, neurological,immunologic and reproductive systems). We have looked atincorporation of traditional assessments of safety pharmacology corebattery assessments for CNS, respiratory and cardiovascular studiesin juvenile toxicity studies. We demonstrate the use of a modifiedfunctional observation battery and whole body plethysmographyto assess effects on CNS and respiratory parameters, respectively,in rats between day 10 and sexual maturation (approximately day50). Whilst beagle dogs approximately 3 to 4 month of age wereinstrumentedwith DSI telemetry transmitters to assess cardiovasculareffect. The data reported illustrate that traditional safety pharmacol-ogy can be adapted to meet the growing requirements for juveniletoxicity studies.
doi:10.1016/j.vascn.2010.11.017
Poster Number: 14Board Number: 14
Measurement of bronchoconstriction in conscious rats: Eleganttechnique, elusive recordingsLorna C. Ewarta, Katherine Elliottb, Michael Haleyb, Tom Hollandb,Sally-Ann Rickettsc, Alan McCarthyb, Lisa Williamsb,Jean-Pierre Valentinb
aAstraZeneca, Macclesfield, Cheshire, United KingdombSafety Assessment, AstraZeneca, Macclesfield, Cheshire, United KingdomcDECS, AstraZeneca, Macclesfield, Cheshire, United Kingdom
Placement of a pressure-sensitive catheter radio-telemetry device,beneath the pleural surface, enables assessment of bronchoconstric-tion in parallel with changes in rate and depth of breathing (Murphyet al. 1998). Here, we assess this approach using an infusion ofmethacholine (MCh) up to 30 μg/kg/min or vehicle (saline) via thetail vein in adapted head-out plethysmography (HOP) chambers.Resistance measured by the telemetric method in conscious male rats(18 Han Wistar, 10 Sprague Dawley) was compared to resistance
Abstracts e5
