Application of an automated natural language processing (NLP) workflow to enable federated search of external biomedical content in drug discovery and development.

External content sources such as MEDLINE(®), National Institutes of Health (NIH) grants and conference websites provide access to the latest breaking biomedical information, which can inform pharmaceutical and biotechnology company pipeline decisions. The value of the sites for industry, however, is limited by the use of the public internet, the limited synonyms, the rarity of batch searching capability and the disconnected nature of the sites. Fortunately, many sites now offer their content for download and we have developed an automated internal workflow that uses text mining and tailored ontologies for programmatic search and knowledge extraction.

Developing timely insights into comparative effectiveness research with a text-mining pipeline.

Comparative effectiveness research (CER) provides evidence for the relative effectiveness and risks of different treatment options and informs decisions made by healthcare providers, payers, and pharmaceutical companies. CER data come from retrospective analyses as well as prospective clinical trials. Here, we describe the development of a text-mining pipeline based on natural language processing (NLP) that extracts key information from three different trial data sources: NIH ClinicalTrials.

Cellular imaging: a key phenotypic screening strategy for predictive toxicology.

Incorporating phenotypic screening as a key strategy enhances predictivity and translatability of drug discovery efforts. Cellular imaging serves as a "phenotypic anchor" to identify important toxicologic pathology that encompasses an array of underlying mechanisms, thus provides an effective means to reduce drug development failures due to insufficient safety. This mini-review highlights the latest advances in hepatotoxicity, cardiotoxicity, and genetic toxicity tests that utilized cellular imaging as a screening strategy, and recommends path forward for further improvement.

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.

This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways.

Biochemical and pharmacological characterization of human c-Met neutralizing monoclonal antibody CE-355621.

The c-Met proto-oncogene is a multifunctional receptor tyrosine kinase that is stimulated by its ligand, hepatocyte growth factor (HGF), to induce cell growth, motility and morphogenesis. Dysregulation of c-Met function, through mutational activation or overexpression, has been observed in many types of cancer and is thought to contribute to tumor growth and metastasis by affecting mitogenesis, invasion, and angiogenesis. We identified human monoclonal antibodies that bind to the extracellular domain of c-Met and inhibit tumor growth by interfering with ligand-dependent c-Met activation.

Comparisons between in vitro whole cell imaging and in vivo zebrafish-based approaches for identifying potential human hepatotoxicants earlier in pharmaceutical development.

Drug-induced liver injury (DILI) is a major cause of attrition during both the early and later stages of the drug development and marketing process. Reducing or eliminating drug-induced severe liver injury, especially those that lead to liver transplants or death, would be tremendously beneficial for patients. Therefore, developing new pharmaceuticals that have the highest margins and attributes of hepatic safety would be a great accomplishment.

Assessment of hepatotoxicity potential of drug candidate molecules including kinase inhibitors by hepatocyte imaging assay technology and bile flux imaging assay technology.

Kinases are members of a major protein family targeted for drug discovery and development. Given the ubiquitous nature of many kinases as well as the broad range of pathways controlled by these enzymes, early safety assessments of small molecule inhibitors of kinases are crucial in identifying new molecules with sufficient therapeutic window for clinical development. Failure or attrition of drug candidates in late-stage pipelines due to hepatotoxicity is a significant challenge in the drug development field.

A predictive ligand-based Bayesian model for human drug-induced liver injury.

Drug-induced liver injury (DILI) is one of the most important reasons for drug development failure at both preapproval and postapproval stages. There has been increased interest in developing predictive in vivo, in vitro, and in silico models to identify compounds that cause idiosyncratic hepatotoxicity. In the current study, we applied machine learning, a Bayesian modeling method with extended connectivity fingerprints and other interpretable descriptors.

Interaction of porphyrins with human organic anion transporting polypeptide 1B1.

The existence of a porphyrin uptake transporter in hepatocytes has been hypothesized in recent years, but to date it has not been identified. While the linear tetrapyrrole bilirubin has been shown to be a substrate for the organic anion transporting polypeptide 1B1 (OATP1B1), similar studies have not been conducted for the cyclic tetrapyrroles (porphyrins). The aim of this study was to determine the structural features of linear and cyclic tetrapyroles necessary for interaction with OATP1B1.

"Seeing is believing": perspectives of applying imaging technology in discovery toxicology.

Efficiency and accuracy in addressing drug safety issues proactively are critical in minimizing late-stage drug attritions. Discovery toxicology has become a specialty subdivision of toxicology seeking to effectively provide early predictions and safety assessment in the drug discovery process. Among the many technologies utilized to select safer compounds for further development, in vitro imaging technology is one of the best characterized and validated to provide translatable biomarkers towards clinically-relevant outcomes of drug safety.

Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity.

Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous, but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF, IFN gamma, IL-1 alpha, and IL-6.

Role of hepatic transporters in the disposition and hepatotoxicity of a HER2 tyrosine kinase inhibitor CP-724,714.

CP-724,714, a potent and selective orally active HER2 tyrosine kinase inhibitor, was discontinued from clinical development due to unexpected hepatotoxicity in cancer patients. Based on the clinical manifestation of the toxicity, CP-724,714 likely exerted its hepatotoxicity via both hepatocellular injury and hepatobiliary cholestatic mechanisms. The direct cytotoxic effect, hepatobiliary disposition of CP-724,714, and its inhibition of active canalicular transport of bile constituents were evaluated in established human hepatocyte models and in vitro transporter systems.

Cellular imaging predictions of clinical drug-induced liver injury.

Drug-induced liver injury (DILI) is the most common adverse event causing drug nonapprovals and drug withdrawals. Using drugs as test agents and measuring a panel of cellular phenotypes that are directly linked to key mechanisms of hepatotoxicity, we have developed an in vitro testing strategy that is predictive of many clinical outcomes of DILI. Mitochondrial damage, oxidative stress, and intracellular glutathione, all measured by high content cellular imaging in primary human hepatocyte cultures, are the three most important features contributing to the hepatotoxicity prediction.

In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone.

Mitochondrial toxicity is increasingly implicated in a host of drug-induced organ toxicities, including hepatotoxicity. Nefazodone was withdrawn from the U.S.

Multiple effects of acetaminophen and p38 inhibitors: towards pathway toxicology.

The majority of drug-related toxicities are idiosyncratic, with little pathophysiological insight and mechanistic understanding. Pathway toxicology is an emerging field of toxicology in the post-genomic era that studies the molecular interactions between toxicants and biological pathways as a way to bridge this knowledge gap. Using two case studies--acetaminophen and p38 MAPK inhibitors--this review illustrates how a pathway-based perspective has advanced our understanding of compound and target-based toxicities.

Differential interaction of 3-hydroxy-3-methylglutaryl-coa reductase inhibitors with ABCB1, ABCC2, and OATP1B1.

The present study examined the interaction of four 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (atorvastatin, lovastatin, and simvastatin in acid and lactone forms, and pravastatin in acid form only) with multidrug resistance gene 1 (MDR1, ABCB1) P-glycoprotein, multidrug resistance-associated protein 2 (MRP2, ABCC2), and organic anion-transporting polypeptide 1B1 (OATP1B1, SLCO21A6). P-glycoprotein substrate assays were performed using Madin-Darby canine kidney (MDCK) cells expressing MDR1, and the efflux ratios [the ratio of the ratio of basolateral-to-apical apparent permeability and apical-to-basolateral permeability between MDR1 and MDCK] were 1.87, 2.

Inhibition of human organic anion transporting polypeptide OATP 1B1 as a mechanism of drug-induced hyperbilirubinemia.

OATP1B1 (a.k.a.

Applications of cytotoxicity assays and pre-lethal mechanistic assays for assessment of human hepatotoxicity potential.

While drug toxicity (especially hepatotoxicity) is the most frequent reason cited for withdrawal of an approved drug, no simple solution exists to adequately predict such adverse events. Simple cytotoxicity assays in HepG2 cells are relatively insensitive to human hepatotoxic drugs in a retrospective analysis of marketed pharmaceuticals. In comparison, a panel of pre-lethal mechanistic cellular assays hold the promise to deliver a more sensitive approach to detect endpoint-specific drug toxicities.

The role of absorption, distribution, metabolism, excretion and toxicity in drug discovery.

Major reasons preventing many early candidates reaching market are the inappropriate ADME (absorption, distribution, metabolism and excretion) properties and drug-induced toxicity. From a commercial perspective, it is desirable that poorly behaved compounds are removed early in the discovery phase rather than during the more costly drug development phases. As a consequence, over the past decade, ADME and toxicity (ADMET) screening studies have been incorporated earlier in the drug discovery phase.