Evaluating Associations Between Nonclinical Cardiovascular Functional Endpoints and Repeat-dose Cardiovascular Toxicity in the Beagle Dog: A Cross-company Initiative.

Integrating nonclinical in vitro, in silico, and in vivo datasets holistically can improve hazard characterization and risk assessment. In pharmaceutical development, cardiovascular liabilities are a leading cause of compound attrition. Prior to clinical studies, functional cardiovascular data are generated in single-dose safety pharmacology telemetry studies, with structural pathology data obtained from repeat-dose toxicology studies with limited concurrent functional endpoints, eg, electrocardiogram via jacketed telemetry. Relationships between datasets remain largely undetermined. To address this gap, a cross-pharma collaboration collated functional and structural data from 135 compounds. Retrospective functional data were collected from good laboratory practice conscious dog safety pharmacology studies: effects defined as hemodynamic blood pressure or heart rate changes. Morphologic pathology findings (mainly degeneration, vacuolation, inflammation) from related toxicology studies in the dog (3-91 days repeat-dosing) were reviewed, harmonized, and location categorized: cardiac muscle (myocardium, epicardium, endocardium, unspecified), atrioventricular/aortic valves, blood vessels. The prevalence of cardiovascular histopathology changes was 11.1% of compounds, with 53% recording a functional blood pressure or heart rate change. Correlations were assessed using the Mantel-Haenszel Chi-square trend test, identifying statistically significant associations between cardiac muscle pathology and (1) decreased blood pressure, (2) increased heart rate, and between cardiovascular vessel pathology and increased heart rate. Negative predictive values were high, suggesting few compounds cause repeat-dose cardiovascular structural change in the absence of functional effects in single-dose safety pharmacology studies. Therefore, observed functional changes could prompt moving (sub)chronic toxicology studies forward, to identify cardiovascular liabilities earlier in development, and reduce late-stage attrition.

The concordance between nonclinical and phase I clinical cardiovascular assessment from a cross-company data sharing initiative.

It is widely accepted that more needs to be done to bring new, safe, and efficacious drugs to the market. Cardiovascular toxicity detected both in early drug discovery as well as in the clinic, is a major contributor to the high failure rate of new molecules. The growth of translational safety offers a promising approach to improve the probability of success for new molecules. Here we describe a cross-company initiative to determine the concordance between the conscious telemetered dog and phase I outcome for 3 cardiovascular parameters. The data indicate that, in the context of the methods applied in this analysis, the ability to detect compounds that affect the corrected QT interval (QTc) was good within the 10-30x exposure range but the predictive or detective value for heart rate and diastolic blood pressure was poor. These findings may highlight opportunities to refine both the animal and the clinical study designs, as well as refocusing the assessment of value of dog cardiovascular assessments beyond phase 1. This investigation has also highlighted key considerations for cross-company data sharing and presents a unique learning opportunity to improve future translational projects.

Comparison of non-invasive and implanted telemetric measurement of blood pressure and electrocardiogram in conscious beagle dogs.

INTRODUCTION: The objective of this study was to evaluate the ability of a non-invasive telemetry monitoring system to detect and quantify changes in blood pressure and electrocardiogram (ECG) parameters in response to vehicle, L-NAME or minoxidil administration to freely moving beagle dogs. Data from a non-invasive telemetry monitoring system were compared to data captured from an invasive telemetry implant in the same animals. METHODS: Blood pressure and ECG data were simultaneously acquired from male dogs using a non-invasive and an invasive implanted telemetry system for 2 hours predose and 24 hours post dosing with vehicle (n=5), minoxidil at 1 mg/kg (n=4) and L-NAME at 10 mg/kg (n=5) on separate test days. Values for mean blood pressure, systolic blood pressure, diastolic blood pressure, pulse pressure, heart rate, RR, PR, QRS, QT and QTcL (heart rate corrected QT interval) interval were reported for both methods. RESULTS: Statistically significant reductions in blood pressure and pulse pressure and increases in heart rate, with associated ECG interval changes were apparent following dosing with minoxidil using both methods. Statistically significant increases in blood pressure and pulse pressure were apparent following dosing with L-NAME when using the invasive telemetry system, changes were apparent when using the non-invasive telemetry system, however, no change was apparent for pulse pressure, they were of shorter duration and not statistically significant. Statistically significant decreases in heart rate, with associated changes in ECG intervals, were apparent following treatment with L-NAME for both invasive and non-invasive methods. DISCUSSION: This study shows that the non-invasive system can be successfully used to acquire both ECG and blood pressure data in freely moving jacketed dogs for at least 26 hours, yet requires further technique refinement to improve system sensitivity to detect smaller changes in blood pressure.

How do the top 12 pharmaceutical companies operate safety pharmacology?

INTRODUCTION: How does safety pharmacology operate in large pharmaceutical companies today? By understanding our current position, can we prepare safety pharmacology to successfully navigate the complex process of drug discovery and development? METHODS: A short anonymous survey was conducted, by invitation, to safety pharmacology representatives of the top 12 pharmaceutical companies, as defined by 2009 revenue figures. A series of multiple choice questions was designed to explore group size, accountabilities, roles and responsibilities of group members, outsourcing policy and publication record. RESULTS: A 92% response rate was obtained. Six out of 11 companies have 10 to 30 full time equivalents in safety pharmacology, who hold similar roles and responsibilities; although the majority of members are not qualified at PhD level or equivalent. Accountabilities were similar across companies and all groups have accountability for core battery in vivo studies and problem solving activities but differences do exist for example with in vitro safety screening and pharmacodynamic/pharmokinetic modeling (PK/PD). The majority of companies outsource less than 25% of studies, with in vitro profiling being the most commonly outsourced activity. Finally, safety pharmacology groups are publishing 1 to 4 articles each year. CONCLUSION: This short survey has highlighted areas of similarity and differences in the way large pharmaceutical companies operate safety pharmacology.

Simulation of multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk.

AIMS: The level of inhibition of the human Ether-à-go-go-related gene (hERG) channel is one of the earliest preclinical markers used to predict the risk of a compound causing Torsade-de-Pointes (TdP) arrhythmias. While avoiding the use of drugs with maximum therapeutic concentrations within 30-fold of their hERG inhibitory concentration 50% (IC(50)) values has been suggested, there are drugs that are exceptions to this rule: hERG inhibitors that do not cause TdP, and drugs that can cause TdP but are not strong hERG inhibitors. In this study, we investigate whether a simulated evaluation of multi-channel effects could be used to improve this early prediction of TdP risk. METHODS AND RESULTS: We collected multiple ion channel data (hERG, Na, L-type Ca) on 31 drugs associated with varied risks of TdP. To integrate the information on multi-channel block, we have performed simulations with a variety of mathematical models of cardiac cells (for rabbit, dog, and human ventricular myocyte models). Drug action is modelled using IC(50) values, and therapeutic drug concentrations to calculate the proportion of blocked channels and the channel conductances are modified accordingly. Various pacing protocols are simulated, and classification analysis is performed to evaluate the predictive power of the models for TdP risk. We find that simulation of action potential duration prolongation, at therapeutic concentrations, provides improved prediction of the TdP risk associated with a compound, above that provided by existing markers. CONCLUSION: The suggested calculations improve the reliability of early cardiac safety assessments, beyond those based solely on a hERG block effect.

Non-invasive telemetric electrocardiogram assessment in conscious beagle dogs.

INTRODUCTION: The primary objective of this investigation was to evaluate the sensitivity of a non-invasive telemetry system for the detection of drug-induced electrocardiogram (ECG) changes in conscious, freely moving dogs. A secondary objective was to compare, in the same set of dogs, ECG data acquired by a non-invasive system with data acquired from a surgically implanted telemetry device (invasive system). METHODS: Continuous beat-to-beat Lead II ECG data were simultaneously acquired from 6 male dogs using a non-invasive and an invasive telemetry system for 1h pre-dose and 6h following a sham control dose or single oral doses of (+/-) sotalol (4, 8 or 16 mg/kg). ECG parameters of heart rate, RR, PQ, QRS, QT and QT corrected for heart rate according to Van de Water (QTcV) and by an individual linear regression formula (QTcR), were determined. RESULTS AND DISCUSSION: Statistically significant dose-dependent reduction of heart rate, and increases in PQ, QT and QTc (V and R) were detected at all dose levels of (+/-) sotalol, with partial recovery during the 6-hour monitoring period. Statistically significant correlations for heart rate, RR, PQ, QT and QTc (V and R) were found between the two systems. QRS duration did not correlate. However, the difference between the two systems was consistent over the range studied. Based on these findings, the non-invasive system is quantitatively comparable to invasive telemetry, and can be used successfully to acquire continuous ECG data on a beat-to-beat basis from conscious freely moving dogs for at least 6h post-dose.

Scientific review and recommendations on preclinical cardiovascular safety evaluation of biologics.

Biological therapeutic agents (biologicals), such as monoclonal antibodies (mAbs), are increasingly important in the treatment of human disease, and many types of biologicals are in clinical development. During preclinical drug development, cardiovascular safety pharmacology studies are performed to assess cardiac safety in accord with the ICH S7A and S7B regulations that guide these studies. The question arises, however, whether or not it is appropriate to apply these guidelines, which were devised primarily to standardize small molecule drug testing, to the cardiovascular evaluation of biologicals. We examined the scientific literature and formed a consensus of scientific opinion to determine if there is a rational basis for conducting an in vitro hERG assay as part of routine preclinical cardiovascular safety testing for biologicals. We conclude that mAb therapeutics have very low potential to interact with the extracellular or intracellular (pore) domains on hERG channel and, therefore, are highly unlikely to inhibit hERG channel activity based on their targeted, specific binding properties. Furthermore, mAb are large molecules (>140,000 Da) that cannot cross plasma membranes and therefore would be unable to access and block the promiscuous inner pore of the hERG channel, in contrast with typical small molecule drugs. Consequently, we recommend that it is not appropriate to conduct an in vitro hERG assay as part of a preclinical strategy for assessing the heart rate corrected QT interval (QTc) prolongation risk of mAbs and other types of biologicals. It is more appropriate to assess QTc risk by integrating cardiovascular endpoints into repeat-dose general toxicology studies performed in an appropriate non-rodent species. These recommendations should help shape future regulatory strategy and discussions for the cardiovascular safety pharmacology testing of mAbs as well as other biologicals and provide guidance for the preclinical cardiovascular evaluation of such agents.