peviva tox picHepatotoxicity and Drug-Induced Liver Injury Detection During Research Use


Peviva Kits Are For Research Use Only

Detecting potential hepatotoxicity is crucial during drug development and drug safety testing in order to reduce the risk of drug candidate withdrawal, and pharmaceuticals showing unwanted hepatic side effects in future surveillance studies.

Standard hepatic injury biomarkers such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), show inadequate sensitivity and specificity with limited predictive value. During pre-clinical drug development, AST/ALT elevations are observed in the absence of hepatic injury. Conversely, tranferases do not increase even when tissue-injury occurs. Around 40 percent of research subjects with drug-induced liver injury (DILI) are not detected in safety studies, and therefore new biomarkers are very much needed.

Ximelagatran was the first orally available direct thrombin inhibitor under development that also reached the market in numerous countries. The drug was tested in an extensive preclinical and clinical program before it was approved and subsequently withdrawn from the market due to hepatotoxicity reports. The preclinical toxicology program in a variety of models, and later short-term use in phase III clinical trials, did not show this hepatotoxicity effect. It wasn’t until long-term use of ximelagatran when increasing hepatic laboratory tests, such as ALT elevations, were observed. The standard preclinical toxicological studies at the time provided no indication that ximelagatran affected hepatic function. How much money was spent? It may not be clear but the average cost of taking a new drug from the bench to the shelf now exceeds $4 billion by some estimates. Clearly there is a need for better biomarkers in drug development.


The Predictive Safety Testing Consortium (PSTC) and International safety program (IMI)

To mitigate the issues with standard liver tests, the PSTC, in collaboration with the IMI, is validating novel liver injury biomarkers. Among the assays of investigation are caspase-cleaved (ccK18) and total keratin 18 (K18), which are studied for application in the regulatory decision making process for use in drug development and as potential drug safety tests.

K18 Research Biomarker Features

Outperforms ALT in specificity when defined as organ of origin
Highly abundant in liver tissue
Minimal day-to-day fluctuations in control samples
Remarkably stable in serum/plasma after sampling
Relatively short half-life in the circulation for examining effects of a drug
Provides informative mechanistic information on hepatocyte injury (apoptosis and/or necrosis)

View our…

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