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Cardiovascular (CV) safety-related attrition is an important contributor to the loss of promising drug candidates during development. CV safety pharmacology studies are conducted to identify these safety effects. Understanding translation of CV endpoints (specifically, heart rate and blood pressure) across preclinical animal models and to the clinic is critical in developing a robust CV derisking strategy. To this end, we investigated translation of heart rate and blood pressure endpoints using data from 83 compounds that were tested in telemetry studies in rat and large animal (LA; dog or monkey) and 79 compounds that were tested in LA telemetry studies and human Phase I clinical trials. Sensitivity, specificity as well as predictive values were calculated for rat to LA model comparison and for LA to human studies comparison. The rat CV model showed good concordance (sensitivity = 84%, specificity = 71%) for LA blood pressure and heart rate changes. Similarly, LA CV measures of heart rate and blood pressure showed good concordance (sensitivity = 78%, specificity = 79%) to clinical changes. The CV effects generally occurred within 0.3 to 3x free plasma concentration across species. Directionality of blood pressure and heart rate change was conserved between LA to humans. However, for rat to LA comparisons the directionality of change was opposite for 23-26% compounds. In conclusion, these data establish the translation of heart rate and blood pressure from preclinical to clinical studies and emphasize the importance of preclinical animal models in the examination of CV safety of drugs.
This article was published in the following journal.
Name: Toxicological sciences : an official journal of the Society of Toxicology
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The branch of pharmacology that deals directly with the effectiveness and safety of drugs in humans.
Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications.
Work that is the report of a pre-planned clinical study of the safety, efficacy, or optimum dosage schedule of one or more diagnostic, therapeutic, or prophylactic drugs, devices, or techniques in humans selected according to predetermined criteria of eligibility and observed for predefined evidence of favorable and unfavorable effects. While most clinical trials concern humans, this publication type may be used for clinical veterinary articles meeting the requisites for humans. Specific headings for specific types and phases of clinical trials are also available.
Pre-planned studies of the safety, efficacy, or optimum dosage schedule (if appropriate) of one or more diagnostic, therapeutic, or prophylactic drugs, devices, or techniques selected according to predetermined criteria of eligibility and observed for predefined evidence of favorable and unfavorable effects. This concept includes clinical trials conducted both in the U.S. and in other countries.
Continuous measurement of the movement and forces of blood in the CARDIOVASCULAR SYSTEM.
Cardiovascular disease (CVD)
Acute Coronary Syndromes (ACS) Blood Cardiovascular Dialysis Hypertension Stent Stroke Vascular Cardiovascular disease (CVD) includes all the diseases of the heart and circulation including coronary heart disease (angina...
Pharmacy is the science and technique of preparing as well as dispensing drugs and medicines. It is a health profession that links health sciences with chemical sciences and aims to ensure the safe and effective use of pharmaceutical drugs. The scope of...