Evaluation of the relevance of DILI predictive hypotheses in early drug development: review of in vitro methodologies vs. BDDCS classification

Abstract

Our published analyses suggest that comparison of proposed DILI prediction methodologies with BDDCS classification is a useful tool to evaluate the potential reliability of newly proposed algorithms, although BDDCS classification itself is not sufficiently predictive. Almost all of the predictive DILI metrics do no better than just avoiding BDDCS Class 2 drugs, although some early data with microliver platforms enabling long-enduring metabolic competency show promising results.

Antimycobacterial, Enzyme Inhibition, and Molecular Interaction Studies of Psoromic Acid in Mycobacterium tuberculosis: Efficacy and Safety Investigations

“…Thus, a prosperous biological effect relies on the relationship between the hydrophilic and hydrophobic properties of the drug or biologically active substances. This is considered an essential aspect for antimycobacterial drugs owing to the presence of a lipid-rich mycobacterial wall [ 44 ]. Although INH showed remarked inhibition properties against all M.tb strains tested with a low Log P value (−0.7), PA exerted potent antimycobacterial activity against all M.tb strains tested with a high Log P value (2.8) ( Table 2 ).…”

The hepatocyte export carrier inhibition assay improves the separation of hepatotoxic from non-hepatotoxic compounds

“…This system also considers the observation that highly permeable substances are often extensively metabolized and this property is associated with a higher risk of developing DILI [37]. BDDCS Class 2 compounds with a low solubility and high permeability are known to be associated with a high DILI risk [37,38]. For DILI prediction the BDDCS class may additionally be combined with the dose (e.g., dose ≥50 mg).…”

Screening Strategies and Methods for Better Off-Target Liability Prediction and Identification of Small-Molecule Pharmaceuticals

“…41,42 The complexity of this and other related mechanisms warrants routine assessment of SMs in advanced mitochondrial cell health assays. 37,38 Beyond kinases, receptors, and other target-relevant protein classes, it is impractical to assume that profiling panels will sufficiently cover the proteome. More importantly, many of these assays lack the appropriate cellular context to fully appreciate the consequences of target engagement since the systems utilized involve isolated proteins or truncated domains and mostly exclude physiologically relevant binding partners.…”

“…41,42 The complexity of this and other related mechanisms warrants routine assessment of SMs in advanced mitochondrial cell health assays. 37,38…”

“…In the case of ETC modulators, inhibitors of complexes I and V do not exhibit acute cytotoxic effects when tested against many primary cell culture systems and often demonstrate favorable effects on anti-inflammatory endpoints. 37,38 However, many inhibitors of these ETC components result in significant toxic liabilities in intact organisms and lead to lactic acidosis. 39 Unique in vitro modulation of complex I had been observed with the marketed drug metformin, including a significant decoupling of redox from proton transfer domains.…”