I’m looking for input regarding the outsourcing of abuse liability testing.  I’m curious as to which models are being used and which contract organizations have offerings and experience in this area.

In models where in-vivo tests are monitored over days and not hours, a tremendous amount of data is generated. How are other researchers handling these large databases and what tools are used to select the subsets of the total data set for analysis?

Does anyone have any suggestions for in vitro or in vivo models to evaluate the potential for a drug to cause pericarditis?

How do others handle the issue of loosing a telemetry animal in a 4×4 Latin square design. For example if you loose one animal after two doses and still have two additional dosing periods.

What is the current practice in the industry when this occurs? One suggestion was to substitute in an animal and simply finish out the study in the normal 4 doses. Another was to substitute in an animal and give 4 more doses. Yet another is to continue on with missing cells. What is your opinion or experience?

I would also like to get the perspective on how you feel these options might impact the statistics.

The SPS will be in its tenth year of existence in 2009 and safety pharmacology as a defined scientific enterprise is also about a decade old. Have we made an impact on the safety of drug development? How is safety pharmacology data viewed by our management in the pharmaceutical industry; are we giving good value for their investments? How are our data being received by regulators? Do we contribute effectively to the safety of early clinical trials? Is our data being taken seriously and is it thought to be predictive by the authorities?

The program committee for the 2009 annual meeting to be held in September in Strasbourg, France is contemplating organizing some programming that will examine this type of question. It should however not only give Safety Pharmacology a ten year “report card” but also look into the future for areas of improvement or expansion.

We’d love to get your input and ideas to give some content to these important questions to help guide us in identifying critical themes and finding appropriate speakers to address them. We may attempt either a panel discussion format or perhaps a debate setting, but regardless of how it turns out, we would appreciate your contribution!

Dear members

Are any of you aware of a realiable supplier of a testing kit for the kidney injury molecule-1 (KIM-1)

Bonventre JV. Kidney Injury Molecule-1 (KIM-1): a specific and sensitive biomarker of kidney
injury. Scand J Clin Lab Invest Suppl. 2008;241:78-83.

Regards
Tomas Mow, Head of Safety Pharmacology, H. Lundbeck.

USDA Policy #3 (Nov 7, 2007) requires the use of pharmaceutical compounds in animals, specifically covered species.  Interested in how other pharmaceutical companies and CROs are handling this new guideline with respect to any and all compounds other than NCEs or NBEs that are administered.  Materials used for analgesia, anesthesia, euthanasia and any animal health medications would most certainly be pharmaceutical grade, but what about reference compounds, competitor compounds and various pharmacological tool compounds used in the performance of many assays?

Consortia collaborations offer a fast and efficient way to develop methods and scientific understanding in principal areas of research. This survey, conducted with the support of the Safety Pharmacology Society, had several objectives: to identify ongoing consortia projects probing areas in the field of safety pharmacology, and to make available to the SPS’s members, information about these programs.

Lessons learned, in terms of managing and contributing in such projects will be presented. The potential role of the SPS as a facilitator of such projects will also be explored.

This will hopefully kick off a discussion about the value of collaborative programs and their potential benefits to the participants.

A survey was e-mailed to members of the SPS. Responseswere collected online. 14 projects involving more than 30 companies were identified. The projects covered the areas of drug-induced pro-arrhythmia (4), drug-induced cardiotoxicity (2), drug dependence and abuse liability (2), cardiovascular genomics (1), study of human ion channels (1), comparative biology and scaling of results across different species (1), and zebra fish as a pre-clinical model (1).

The SPS is in a unique position to take the lead by collecting and disseminating information about consortia projects (both completed and in-progress) and identifying new areas where further research is needed. Creation of Special Working Groups around specific topics under the auspices of the SPS could serve to facilitate consortia projects to the benefit of patients, safety pharmacologists, the society, and regulatory bodies alike.

Prior to candidate recommendation from discovery, most groups conduct some sort of “ancillary” cardiovascular study. The question is in what model?

Could folks share the in vivo model or models that are typically used (eg. dog, monkey, rat, conscious/anesthetized, etc) to support the advancement of a compound into the toxicology phase of development.  Also, if any models used are established in the company, or outsourced.

The electrocardiogram is taken routinely in conjunction with toxicological studies in larger animal species including the dog, primate or pig. They have been used in the past to document heart rate as well as to identify gross electrocardiographic changes that might occur over time due to such things as myocardial ischemia or myocardial hypertrophy.

Due to the recent attention to the detection of drug-induced effects on ventricular repolarization, there is an increased interest in analyzing ECGs more thoroughly to include the standard intervals and wave form durations. Of particular note is the meausrement of the QT interval for detecting hERG-induced delays in ventricular repolarization. The ICHS7a guideline suggests that in vivo evaluation of the potential for drugs to prolong the QT interval might be addressed in toxicological studies.

Over the past years there has been an increased awareness of the challenges involved in doing a high quality preclinical, in vivo evaluation of potential effects on ventricular repolarization. The important role of heart rate-induced effects on repolarization must be taken into account. We know now that various physiolgoical factors can affect the QT interval. Furthermore, the sensitivity of a given test system to pick up a given change in the QT interval is dependent upon the variability of the measured parameter. Above all, a robust evaluation of the potential effects of a drug on ventricular repolarization requires a high quality ECG, at best recorded frequently enough to allow for a thorough analysis of time-dependent effects.

The question posed here is whether or not the quality of ECGs, as have been taken routinely in the past (and still presently) are adequate for a reliable assessment of drug-induced prolongation of the QT interval?

Have you evaluated ECGs from toxicological studies and been satisfied with their quality?

Is the amount of data collected in “traditional” tox studies sufficent to base such an assessment?

Are the animals used in a tox study in an acceptable physiological state to consider them for use in a “non-clinical QT study?”

Do you know of anyone who has done a power analysis on ECG data coming from a tox study? What size of effect on QT can one reasonably detect with the number of animals typicllyused for tox studies?

What is feasible to improve quality of ECGs in tox studies and what are the associated costs and efforts needed to affect an increased quality? Would most sponsors be willing to invest to improve this readout?

We would appreciate hearing about your experiences and opinions on this matter!