Biomarkers
dysfunctional if left untreated. The natriuretic pep- tides are cardiac neurohormones that are released from the atrial and ventricular myocardium in response to increased wall stress: Atrial natriuretic peptide (ANP) and its amino-terminal fragments (NT-proANP) are released primarily from the atria; Brain natriuretic peptide (BNP) and its N-ter- minal fragments (NT-proBNP), are predominantly released from the ventricular cardiomyocytes (Figure 2). BNP is gaining acceptance within the industry as a biomarker for diagnosing congestive heart failure.
BNP is involved in many physiologic functions including natriuresis, diuresis, vasodilation, inhibi- tion of sympathetic tone, inhibition of the renin- angiotensin-aldosterone system (RAAS), and inhi- bition of endothelin-1. The release of BNP directly correlates with the degree of ventricular wall ten- sion, reflecting disease severity and prognosis. It has been suggested, however, that measuring NT- proBNP may be of greater clinical utility because its half-life is much longer than that of BNP (120 minutes versus 22 minutes) in humans. This also holds true in veterinary medicine, and is supported by recent studies showing that the assessment of NT-proBNP may be useful in identifying cardiac disease in dogs and grading disease severity.
An integrative approach
The ability to determine the serum levels of tro- ponins and natriuretic peptides (NT-proBNP and NT-proANP) in a preclinical assessment would allow for the early identification of cardiovascular liability and would prevent unexpected drug- induced adverse effects in clinical trials during the late stages of drug development. The use of these biomarkers, which have been widely accepted in the clinical setting, could reduce the health risks for patients and healthy volunteers.
One approach to the issue of cardiotoxicity early in preclinical development is through the integra- tion of several investigational tools, including the measurement of serum biomarkers (troponins and natriuretic peptides) in conjunction with other heart parameters such as heart weight relative to body weight (standard evaluation of cardiac hyper- trophy), standard examinations (ie, histopatholo- gy) and non-standard endpoints (ie, echocardiog- raphy and macroscopic morphometry). Casopitant is a potent and selective antagonist of the human neurokinin 1 (NK1) receptor which was developed for the chronic treatment of depression and anxiety, and was under investigation (and later withdrawn) for the prevention of chemotherapy- induced and post-operative nausea and vomiting.
Drug Discovery World Summer 2011
Casopitant was found to cause cardiotoxicity after long-term toxicity studies in late-stage drug devel- opment. In a 39-week dog study, oral administra- tion of casopitant caused increased heart weight and myocardial necrosis, degeneration, inflamma- tion and phospholipidosis. Previous short-term studies up to 13 weeks in duration suggested that casopitant was extensively metabolised and retained for longer periods in tissues, but cardiac changes were limited to a minimal increase of heart weight. Thus, drug tissue accumulation with chronic administration was responsible for late- onset toxicity, and the cardiac changes were only evident following long-term observation in dogs. An integrated assessment of the onset and pro- gression of the cardiotoxicity was conducted to provide insights for risk assessment, to aid in the identification of early translational biomarkers of cardiotoxicity, and to support decision making. The integration of different disciplines and multi- ple tools across various early time points consti- tuted a powerful approach for the characterisa- tion of casopitant-induced cardiotoxicity in pre- clinical development. Together with transmission electron microscopy (TEM) and metabolite tissue accumulation, serum cTnI provided early evidence of cardiac cell necro- sis starting from six weeks of treatment and these lesions increased in severity over time, suggesting a progressive impairment of the cardiomyocytes. An increase in heart weight, left ventricular (LV) mass, wall thickening, heart rate and prolongation of the QT interval were also observed after six weeks of treatment. Serum levels of NT-proBNP, on the other hand, were increased after only two weeks of casopitant treatment (Figure 3), preceding all of the anatomical and functional changes observed. In addition, LV mass, QTc interval and heart rate all recovered following treatment withdrawal; NT- proBNP did not return to normal values even after 22 weeks of withdrawal. This finding supports the sensitivity of NT-proBNP as an early prognostic biomarker of cardiotoxicity, indicating drug- induced cardiac mass changes and hemodynamic stress, and represents a potentially useful tool for clinical risk mitigation.
This case highlights the limitations in terms of sensitivity of the standard regulatory toxicity studies, and suggests that the increased use of non-conventional tools could better characterise new drug candidates. NT-proBNP changes pre- ceded all anatomical and functional changes and served as an early biomarker of cardiac hyper- trophy even in the absence of evidence of func- tional impairment. The results support the use of
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