Limitations Faced In Preclinical Safety Assessment

A critical problem faced by nonclinical safety assessment groups in pharmaceutical drug development is the disparity of responses sometimes seen between the two nonclinical test species in the tools used to assess these responses. Historically, microscopic histopathology is used as a primary tool for identifying compound--nduced damage. When damage is identified only at exposures far exceeding those expected in clinical studies, clinical safety is expected. However, microscopic histopathology is not a tool generally applicable to human studies, where clinical pathology measurements play the criti cal role in assessing adverse responses to drugs. Thus, if damage is observed in one nonclinical species at exposures close to those anticipated for human studies, the crucial question is whether the onset and reversibility of such damage could be monitored with clinical pathology or some other relatively noninvasive technology. Unfortunately, as described here, there are several types of drug-induced organ injury where current clinical pathology assays do not detect damage with sufficient certainty at early stages, and where assurances are needed that discontinuation of drug treatment would be followed by a complete and swift return to normal structure and function.

Kidney Injury

Kidney injury may be produced by a variety of insults, including those induced by drugs or toxicants [10]. Given the known morbidity and mortality associated with acute kidney injury [11,12], evidence of drug-induced kidney injury in preclinical studies is a matter of serious concern. While on one hand the kidney is capable of recovery from mild damage [13] if the injurious agent is removed, the very real clinical problem is that traditional noninvasive measures of kidney function are insensitive and confounded by many factors [13-16] . Thus, even modest increases in serum creatinine are associated with significant mortality [12] . There is a real need for noninvasive markers that would detect kidney damage or loss of function at a stage before significant and irreversible damage has occurred. Several markers with just such a potential have been described in numerous reviews [13-20]. However, many of these are described in relatively few clinical studies, most have not been examined carefully for their performance in animal models of drug-induced kidney injury, and no consensus understanding between drug development sponsors and regulatory review authorities had been reached as to their utility for regulatory decision-making purposes. Ultimately, if a microscopic histopathologi-cal examination shows evidence of even mild drug-induced kidney injury in a preclinical study at exposures close to those anticipated for clinical use, development of that compound may be stopped, even if human relevance may be questioned, yet unproven.

Liver Injury

The fact that medicines can cause liver injury and failure has been appreciated for some time - 21] . and drug - -nduced liver injury remains a serious public health and drug development concern [22-25]. As with other drug-induced organ damage, it may be detected in preclinical studies through microscopic histopathology and clinical chemistry measurements. Since the late 1950s, serum transaminase measurements, in particular that of alanine aminotrans-ferase (ALT), have served as a sensitive and less - -nvasive measure of liver damage in both animal and human settings [26] - In conjunction with serum cholesterol, bilirubin, alkaline phosphatase, and other factors, ALT has served as a translational biomarker for drug-induced liver injury [27-30] . However, ALT elevations are not always associated with clear evidence of liver injury [31-33] . and ALT elevations cannot clearly indicate the etiology of damage [26,27,30,34]. Furthermore, ALT measurements either alone or with bilirubin cannot distinguish patients on a trajectory to severe liver disease and inability to heal or recover from injury, from patients with a full capacity to compensate and return ALT levels to normal despite continuation of drug dosing [ 35]. Combinations of clinical pathology changes have been used, including ALT and bilirubin, to assure safety in clinical trials [36] but there remains a need for diagnostic assays that reliably link and/or predict the histological observation of liver injury in both a preclinical and clinical setting, and discriminate the types and trajectory of apparent injury [30].

Vascular Injury

Although injury to the vascular system is known to be caused by a variety of agents [ 37], many classes of therapeutic agents produce vascular lesions, in preclinical species with or without clinical signs, and with normal routine clinical pathology data [38]. Often, different preclinical species show a different level and type of response, and in many cases (e.g., minoxidil) the vascular injury reported in preclinical species is not observed in a clinical setting [39]. Drug- i nduced vascular injury in animals may result from altered hemody-namic forces, from a direct chemical-mediated injury to cells of the vascula-ture, and/or to an indirect immune-mediated injury of the endothelium and/ or medial smooth muscle. The conundrum faced in drug development is that there are no specific and sensitive biomarkers of endothelial and/or vascular smooth muscle injury that are clearly linked to the histological observations in animals and could be used to monitor for injury in clinical settings. Although it is assumed that an inflammatory component may be active at some stage in this process, and biomarkers are proposed for such processes [40], biomarkers that are sufficiently sensitive at early and fully reversible stages of vascular injury have not been fully evaluated .38,41] . Furthermore, specific markers of vascular injury/inflammation are sought that can discriminate from the multitude of other more benign causes for elevations of inflammatory biomarkers.

Drug-Induced Skeletal Myopathy

With the introduction of hydroxymethylglutaryl-coenzyme A (HMG- CoA) reductase inhibitors (statins), not only was there a successful treatment of hypercholesterolemia and dyslipidemia, but soon also a heightened awareness of the issue of drug-induced myopathy [42]. Statin-induced myotoxicity ranges from mild myopathy to serious and sometimes fatal rhabdomyolysis. Not surprisingly, a variety of drugs have been reported to induce myotoxicities

[43]. While skeletal muscle toxicity may be monitored with elevations in serum creatinine kinase (CK), urinary myoglobin, and other markers [42], these biomarkers lack the sensitivity to definitively diagnose early damage or to distinguish the various etiologies of the muscle injury -43] - Thus, there is a need for markers of drug--nduced muscle injury with improved sensitivity, specificity, and general utility.

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