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

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.

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!