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Abstract: Drug safety has always been a key aspect of drug development. Recently, the Vioxx case and several cases of serious adverse events being linked to high-profile products have increased the importance of drug safety, especially in the eyes of drug development companies and global regulatory agencies. Safety biomarkers are increasingly being seen as helping to provide the clarity, predictability, and certainty needed to gain confidence in decision making: early-stage projects can be stopped quicker, late-stage projects become less risky. Public and private organizations are investing heavily in terms of time, money and manpower on safety biomarker development. An illustrative and “door opening” safety biomarker success story is the recent recognition of kidney safety biomarkers for pre-clinical and limited translational contexts by FDA and EMEA. This milestone achieved for kidney biomarkers and the “know how” acquired is being transferred to other organ toxicities, namely liver, heart, vascular system. New technologies and molecular-based approaches, i.e., molecular pathology as a complement to the classical toolbox, allow promising discoveries in the safety biomarker field. This review will focus on the utility and use of safety biomarkers all along drug development, highlighting the present gaps and opportunities identified in organ toxicity monitoring. A last part will be dedicated to safety biomarker development in general, from identification to diagnostic tests, using the kidney safety biomarkers success as an illustrative example. [Copyright &y& Elsevier]

What conductors are to their orchestras, biomarkers are to their associated technologies. Building fundamental science, supporting early diagnosis of diseases and following their progression, improving efficacy and safety of treatments, optimizing patient selection and adapting dosing of drugs, helping decide which therapy is most appropriate; these are examples of a few contexts in which biomarkers are key players. Technology development can definitely not escape being associated with these steps. In other words, today’s biomarkers are the thermometers of tomorrow’s therapies. This review provides an overview of recently established platforms as well as new and upcoming technologies for biomarker development in the context of drug development. The roles as well as the pros and cons of different disciplines such as genetics, genomics, proteomics, metabonomics, and assay development will be discussed. [ABSTRACT FROM AUTHOR]

Biomarkers have been a buzz word in drug development for the last 5 years. But where do we stand now? This perspective article will demonstrate to which extent biomarkers have impacted drug development and the use of drugs. In particular, the different types of biomarkers, their identification, validation and use in different phases of drug development from drug discovery, to approval, to clinical application will be discussed as well as the state-of-the-art biomarker technologies and promising future methods. The high interest in biomarkers has generated the need for development of new technologies and refinement of existing ones. Besides discussing their perspectives of applications, the present article also illustrates the future of biomarker development in terms of qualification for regulatory use and co-development. [ABSTRACT FROM AUTHOR]

Abstract: In vitro, concentrations ≥10μM of nilotinib were needed to induce markers of cytotoxicity, apoptosis, and endoplasmic reticulum stress in both neonatal rat ventricular myocytes, a putative target tissue, and non-target heart fibroblasts, indicating a lack of cardiomyocyte-specific nilotinib toxicity in vitro. In rats, oral nilotinib treatment at 80mg/kg for 4 weeks induced increased heart weight; however, this was not associated with relevant histopathological changes or effects on heart function. Thus, nilotinib at and above clinically relevant concentrations (4.27μM) did not induce overt cardiovascular pathologies or heart failure in vitro or in vivo under study conditions. [Copyright &y& Elsevier]

Abstract: Cytotoxic concentrations of imatinib mesylate (10–50μM) were required to trigger markers of apoptosis and endoplasmic reticulum stress response in neonatal rat ventricular myocytes and fibroblasts, with no significant differences observed between c-Abl silenced and nonsilenced cells. In mice, oral or intraperitoneal imatinib treatment did not induce cardiovascular pathology or heart failure. In rats, high doses of oral imatinib did result in some cardiac hypertrophy. Multi-organ toxicities may have increased the cardiac workload and contributed to the cardiac hypertrophy observed in rats only. These data suggest that imatinib is not cardiotoxic at clinically relevant concentrations (5μM). [ABSTRACT FROM AUTHOR]

Kidney toxicity accounts both for the failure of many drug candidates as well as considerable patient morbidity. Whereas histopathology remains the gold standard for nephrotoxicity in animal systems, serum creatinine (SCr) and blood urea nitrogen (BUN) are the primary options for monitoring kidney dysfunction in humans. The transmembrane tubular protein kidney injury molecule-1 (Kim-1) was previously reported to be markedly induced in response to renal injury. Owing to the poor sensitivity and specificity of SCr and BUN, we used rat toxicology studies to compare the diagnostic performance of urinary Kim-1 to BUN, SCr and urinary N-acetyl-β-D-glucosaminidase (NAG) as predictors of kidney tubular damage scored by histopathology. Kim-1 outperforms SCr, BUN and urinary NAG in multiple rat models of kidney injury. Urinary Kim-1 measurements may facilitate sensitive, specific and accurate prediction of human nephrotoxicity in preclinical drug screens. This should enable early identification and elimination of compounds that are potentially nephrotoxic. [ABSTRACT FROM AUTHOR]