Hepatotoxicity reports in the FDA adverse event reporting system database: A comparison of drugs that cause injury via mitochondrial or other mechanisms

Drug-induced liver injury (DILI) is a leading reason for preclinical safety attrition and post-market drug withdrawals. Drug-induced mitochondrial toxicity has been shown to play an essential role in various forms of DILI, especially in idiosyncratic liver injury. This study examined liver injury reports submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) for drugs associated with hepatotoxicity via mitochondrial mechanisms compared with non-mitochondrial mechanisms of toxicity. The frequency of hepatotoxicity was determined at a group level and individual drug level. A reporting odds ratio (ROR) was calculated as the measure of effect. Between the two DILI groups, reports for DILI involving mitochondrial mechanisms of toxicity had a 1.43 (95% CI 1.42–1.45; P \u3c 0.0001) times higher odds compared to drugs associated with non-mitochondrial mechanisms of toxicity. Antineoplastic, antiviral, analgesic, antibiotic, and antimycobacterial drugs were the top 5 drug classes with the highest ROR values. Although the top 20 drugs with the highest ROR values included drugs with both mitochondrial and non-mitochondrial injury mechanisms, the top 4 drugs (ROR values \u3e18: benzbromarone, troglitazone, isoniazid, rifampin) were associated with mitochondrial mechanisms of toxicity. The major demographic influence for DILI risk was also examined. There was a higher mean patient age among reports for drugs that were associated with mitochondrial mechanisms of toxicity [56.1 ± 18.33 (SD)] compared to non-mitochondrial mechanisms [48 ± 19.53 (SD)] (P \u3c 0.0001), suggesting that age may play a role in susceptibility to DILI via mitochondrial mechanisms of toxicity. Univariate logistic regression analysis showed that reports of liver injury were 2.2 (odds ratio: 2.2, 95% CI 2.12–2.26) times more likely to be associated with older patient age, as compared with reports involving patients less than 65 years of age. Compared to males, female patients were 37% less likely (odds ratio: 0.63, 95% CI 0.61–0.64) to be subjects of liver injury reports for drugs associated with mitochondrial toxicity mechanisms. Given the higher proportion of severe liver injury reports among drugs associated with mitochondrial mechanisms of toxicity, it is essential to understand if a drug causes mitochondrial toxicity during preclinical drug development when drug design alternatives, more clinically relevant animal models, and better clinical biomarkers may provide a better translation of drug-induced mitochondrial toxicity risk assessment from animals to humans. Our findings from this study align with mitochondrial mechanisms of toxicity being an important cause of DILI, and this should be further investigated in real-world studies with robust designs

Most Influential Physicochemical and in Vitro Assay Descriptors for Hepatotoxicity and Nephrotoxicity Prediction

Drug-induced organ injury is a major reason for drug candidate attrition in preclinical and clinical drug development. The liver, kidneys, and heart have been recognized as the most common organ systems affected in safety-related attrition or the subject of black box warnings and postmarket drug withdrawals. In silico physicochemical property calculations and in vitro assays have been utilized separately in the early stages of the drug discovery and development process to predict drug safety. In this study, we combined physicochemical properties and in vitro cytotoxicity assays including mitochondrial dysfunction to build organ-specific univariate and multivariable logistic regression models to achieve odds ratios for the prediction of clinical hepatotoxicity, nephrotoxicity, and cardiotoxicity using 215 marketed drugs. The multivariable hepatotoxic predictive model showed an odds ratio of 6.2 (95% confidence interval (CI) 1.7-22.8) or 7.5 (95% CI 3.2-17.8) for mitochondrial inhibition or drug plasma Cmax \u3e1 μM for drugs associated with liver injury, respectively. The multivariable nephrotoxicity predictive model showed an odds ratio of 5.8 (95% CI 2.0-16.9), 6.4 (95% CI 1.1-39.3), or 15.9 (95% CI 2.8-89.0) for drug plasma Cmax \u3e1 μM, mitochondrial inhibition, or hydrogen-bond-acceptor atoms \u3e7 for drugs associated with kidney injury, respectively. Conversely, drugs with a total polar surface area ≥75 Å were 79% (odds ratio 0.21, 95% CI 0.061-0.74) less likely to be associated with kidney injury. Drugs belonging to the extended clearance classification system (ECCS) class 4, where renal secretion is the primary clearance mechanism (low permeability drugs that are bases/neutrals), were 4 (95% CI 1.8-9.5) times more likely to to be associated with kidney injury with this data set. Alternatively, ECCS class 2 drugs, where hepatic metabolism is the primary clearance (high permeability drugs that are bases/neutrals) were 77% less likely (odds ratio 0.23 95% CI 0.095-0.54) to to be associated with kidney injury. A cardiotoxicity model was poorly defined using any of these drug physicochemical attributes. Combining in silico physicochemical properties descriptors along with in vitro toxicity assays can be used to build predictive toxicity models to select small molecule therapeutics with less potential to cause liver and kidney organ toxicity

Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals

The role of bile salt export protein (BSEP) inhibition in drug-induced liver injury (DILI) has been investigated widely, while inhibition of the canalicular multidrug resistant protein 3 (MDR3) has received less attention. This transporter plays a pivotal role in secretion of phospholipids into bile and functions coordinately with BSEP to mediate the formation of bile acid-containing biliary micelles. Therefore, inhibition of MDR3 in human hepatocytes was examined across 125 drugs (70 of Most-DILI-concern and 55 of No-DILI-concern). Of these tested, 41% of Most-DILI-concern and 47% of No-DILI-concern drugs had MDR3 IC₅₀ values of <50 μM. A better distinction across DILI classifications occurred when systemic exposure was considered where safety margins of 50-fold had low sensitivity (0.29), but high specificity (0.96). Analysis of physical chemical property space showed that basic compounds were twice as likely to be MDR3 inhibitors as acids, neutrals, and zwitterions and that inhibitors were more likely to have polar surface area (PSA) values of <100 Ų and cPFLogD values between 1.5 and 5. These descriptors, with different cutoffs, also highlighted a group of compounds that shared dual potency as MDR3 and BSEP inhibitors. Nine drugs classified as Most-DILI-concern compounds (four withdrawn, four boxed warning, and one liver injury warning in their approved label) had intrinsic potency features of <20 μM in both assays, thereby reinforcing the notion that multiple inhibitory mechanisms governing bile formation (bile acid and phospholipid efflux) may confer additional risk factors that play into more severe forms of DILI as shown by others for BSEP inhibitors combined with multidrug resistance-associated protein (MRP2, MRP3, MRP4) inhibitory properties. Avoiding physical property descriptors that highlight dual BSEP and MDR3 inhibition or testing drug candidates for inhibition of multiple efflux transporters (e.g., BSEP, MDR3, and MRPs) may be an effective strategy for prioritizing drug candidates with less likelihood of causing clinical DILI

Improving the Odds of Success in Drug Discovery: Choosing the Best Compounds for in Vivo Toxicology Studies

A set of molecules that advanced into exploratory animal toxicology studies (two species) was examined to determine what properties contributed to success in these safety studies. Compounds were rigorously evaluated across numerous safety end points and classified as “pass” if a suitable in vivo therapeutic index (TI) was achieved for advancement into regulatory toxicology studies. The most predictive end point contributing to compound survival was a predicted human efficacious concentration (<i>C</i>_eff) of ≤250 nM (total drug) and ≤40 nM (free drug). This trend held across a wide range of CNS modes of action, encompassing targets such as enzymes, G-protein-coupled receptors, ion channels, and transporters

Copper(I) Halides (X = Br, I) Coordinated to Bis(arylthio)methane Ligands: Aryl Substitution and Halide Effects on the Dimensionality, Cluster Size, and Luminescence Properties of the Coordination Polymers

Bis­(phenylthio)­methane (<b>L1</b>) reacts with CuI to yield the 1D-coordination polymer [{Cu₄(μ₃-I)₄}­(μ-<b>L1</b>)₂]_<i>n</i> (<b>1</b>) bearing cubane Cu₄I₄ clusters as connecting nodes. The crystal structures at 115, 155, 195, and 235 K provided evidence for a phase transition changing from the monoclinic space group <i>C</i>2/<i>c</i> to <i>P</i>2₁/<i>c</i>. The self-assembly process of CuI with bis­(<i>p</i>-tolylthio)­methane (<b>L2</b>), bis­(4-methoxyphenylthio)­methane (<b>L3</b>), and bis­(4-bromo-phenylthio)­methane (<b>L4</b>) affords the 1D-coordination polymers [{Cu₄(μ₃-I)₄}­(μ-<b>L<i>x</i></b>)₂]_<i>n</i> (<i>x</i> = 2, 3, or 4). Compounds <b>2</b> and <b>4</b> are isostructural with <i>C</i>2/<i>c</i> low temperature polymorph of <b>1</b>, whereas the inversion centers and 2-fold axes are lost in <b>3</b> (space group <i>Cc</i>). The use of bis­(<i>m</i>-tolylthio)­methane (<b>L5</b>) has no impact on the composition and overall topology of the resulting 1D ribbon of [{Cu₄(μ₃-I)₄}­(μ-<b>L5</b>)₂]_<i>n</i> (<b>5</b>). Even the coordination of the sterically crowded dithioether bis­(5-<i>tert</i>-butyl-2-methylphenylthio)­methane (<b>L8</b>) does not alter the network topology generating the 1D polymer [{Cu₄(μ₃-I)₄}­(μ-<b>L8</b>)₂]_<i>n</i> (<b>8</b>). The 1D polymer [{Cu­(μ₂-Br)₂Cu}­(<b>L1</b>)₂] (<b>9</b>) results from the coordination of <b>L1</b> with CuBr in a 1:1 metal-to-ligand ratio. In contrast to the mean Cu···Cu distances, which are <2.8 Å noted for the Cu₄(μ₃-I)₄ clusters in the 1D polymers <b>1</b>–<b>8</b>, the Cu···Cu contact within the Cu­(μ₂-Br)₂Cu rhomboids of <b>9</b> [2.9194(8) Å] is above the sum of the van der Waals radii of two Cu atoms. The structural arrangement of 1D polymer [{Cu­(μ₂-Br)₂Cu}­(<b>L3</b>)₂]_<i>n</i> (<b>11</b>) is quite similar to that of <b>9</b>. While the reaction of CuBr with <b>L5</b> results in a similar 1D polymer [{Cu­(μ₂-Br)₂Cu}­(<b>L5</b>)₂]_<i>n</i> (<b>12</b>), the reaction of CuBr with <b>L2</b> leads to the dinuclear complex [{Cu­(μ₂-Br)₂Cu}­(η¹-<b>L2</b>)₄] (<b>10</b>) ligated by four pendent bis­(<i>p</i>-tolylthio)­methane ligands. The ligation of bis­(<i>o</i>-tolylthio)­methane, <b>L6</b>, on CuBr also yields a discrete complex [{Cu­(μ₂-Br)₂Cu}­(MeCN)₂(η¹-<b>L6</b>)₂] (<b>13</b>) bearing MeCN and dangling dithioether ligands. A strong luminescence is detected for all CuI polymers, all exhibiting emission lifetimes in the microsecond time scale (i.e., phosphorescence). The polymers containing the Cu₄I₄ core (<b>1</b>–<b>8</b>) exhibit the typically observed low-energy band and sometimes a weaker high-energy band. The nature of the low-energy band was proposed based on literature DFT and TDDFT computations and is predicted to be a mixture of cluster-centered (CC*) and metal/halide-to-ligand charger transfer (M/XLCT). An approximate relationship between the Cu···Cu distance and the emission maxima corroborates the CC* contribution to the nature of the excited states. The emission of the rhomboid-containing materials is assigned to M/XLCT based on literature works on similar motifs

CHANGES OF SOLAR CELL PARAMETERS DURING DAMP-HEAT EXPOSURE

The degradation of PV modules during damp-heat exposure is investigated. Power degradation is analysed in dependence of temperature and humidity during exposure. The module’s equivalent circuit parameters are calculated from I-V characteristics measured during ageing. A dose function is developed and degradations of power as well as equivalent circuit parameters can be analysed against the dose, which provides a better understanding of the module ageing behaviour. EL images of modules before and after ageing support the changes of solar cell parameters.JRC.F.7-Renewables and Energy Efficienc