Bile salt export pump (BSEP) inhibition has emerged as an important mechanism that may contribute to the initiation of human drug‐induced liver injury (DILI). Proactive evaluation and understanding of BSEP inhibition is recommended in drug discovery and development to aid internal decision making on DILI risk. BSEP inhibition can be quantified using in vitro assays. When interpreting assay data, it is important to consider in vivo drug exposure. Currently, this can be undertaken most effectively by consideration of total plasma steady state drug concentrations (Css,plasma). However, because total drug concentrations are not predictive of pharmacological effect, the relationship between total exposure and BSEP inhibition is not causal. Various follow‐up studies can aid interpretation of in vitro BSEP inhibition data and may be undertaken on a case‐by‐case basis. BSEP inhibition is one of several mechanisms by which drugs may cause DILI, therefore, it should be considered alongside other mechanisms when evaluating possible DILI risk.

Drug-induced liver injury (DILI) is a major cause of late-stage clinical drug attrition, market withdrawal, black-box warnings, and acute liver failure. Consequently, it has been an area of focus for toxicologists and clinicians for several decades. In spite of considerable efforts, limited improvements in DILI prediction have been made and efforts to improve existing preclinical models or develop new test systems remain a high priority. While prediction of intrinsic DILI has improved, identifying compounds with a risk for idiosyncratic DILI (iDILI) remains extremely challenging because of the lack of a clear mechanistic understanding and the multifactorial pathogenesis of idiosyncratic drug reactions. Well-defined clinical diagnostic criteria and risk factors are also missing. This paper summarizes key data interpretation challenges, practical considerations, model limitations, and the need for an integrated risk assessment. As demonstrated through selected initiatives to address other types of toxicities, opportunities exist however for improvement, especially through better concerted efforts at harmonization of current, emerging and novel in vitro systems or through the establishment of strategies for implementation of preclinical DILI models across the pharmaceutical industry. Perspectives on the incorporation of newer technologies and the value of precompetitive consortia to identify useful practices are also discussed.

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In vitro assays are commonly used during drug discovery to try to decrease the risk of idiosyncratic drug-induced liver injury (iDILI). But how effective are they at predicting risk? One of the most widely used methods evaluates cell cytotoxicity. Cytotoxicity assays that used cell lines that are very different from normal hepatocytes, and high concentrations of drug, were not very accurate at predicting idiosyncratic drug reaction risk. Even cytotoxicity assays that use more biologically normal cells resulted in many false-positive and false-negative results. Assays that quantify reactive metabolite formation, mitochondrial injury, and bile salt export pump (BSEP) inhibition have also been described. Although evidence suggests that reactive metabolite formation and BSEP inhibition can play a role in the mechanism of iDILI, these assays are not very accurate at predicting risk. In contrast, inhibition of the mitochondrial electron transport chain appears not to play an important role in the mechanism of iDILI, although other types of mitochondrial injury may do so. It is likely that there are many additional mechanisms by which drugs can cause iDILI. However, simply measuring more parameters is unlikely to provide better predictive assays unless those parameters are actually involved in the mechanism of iDILI. Hence, a better mechanistic understanding of iDILI is required; however, mechanistic studies of iDILI are very difficult. There is substantive evidence that most iDILI is immune mediated; therefore, the most accurate assays may involve those that determine immune responses to drugs. New methods to manipulate immune tolerance may greatly facilitate development of more suitable methods.

Imaging technologies can evaluate many different biological processes in vitro (in cell culture models) and in vivo (in animals and humans), and many are used routinely in investigation of human liver diseases. Some of these methods can help understand liver toxicity caused by drugs in vivo in animals, and druginduced liver injury (DILI) which arises in susceptible humans. Imaging could aid assessment of the relevance to humans in vivo of toxicity caused by drugs in animals (animal/human translation), plus toxicities observed using in vitro model systems (in vitro/in vivo translation). Technologies and probe substrates for quantitative evaluation of hepatobiliary transporter activities are of particular importance. This is due to the key role played by sinusoidal transporter mediated hepatic uptake in DILI caused by many drugs, plus the strong evidence that inhibition of the hepatic bile salt export pump (BSEP) can initiate DILI. Imaging methods for investigation of these processes are reviewed in this chapter, together with their scientific rationale, and methods of quantitative data analysis. In addition to providing biomarkers for investigation of DILI, such approaches could aid the evaluation of clinically relevant drug-drug interactions mediated via hepatobiliary transporter perturbation.

Background A large proportion of surgical patient harm is preventable; yet, our ability to systematically learn from these incidents and improve clinical practice remains limited. The Operating Room Black Box was developed to address the need for comprehensive assessments of clinical performance in the operating room. It captures synchronized audio, video, patient, and environmental clinical data in real time, which are subsequently analyzed by a combination of expert raters and software-based algorithms. Despite its significant potential to facilitate research and practice improvement, there are many potential implementation challenges at the institutional, clinician, and patient level. This paper summarizes our approach to implementation of the Operating Room Black Box at a large academic Canadian center. Objective We aimed to contribute to the development of evidence-based best practices for implementing innovative technology in the operating room for direct observation of the clinical performance by using the case of the Operating Room Black Box. Specifically, we outline the systematic approach to the Operating Room Black Box implementation undertaken at our center. Methods Our implementation approach included seeking support from hospital leadership; building frontline support and a team of champions among patients, nurses, anesthesiologists, and surgeons; accounting for stakeholder perceptions using theory-informed qualitative interviews; engaging patients; and documenting the implementation process, including barriers and facilitators, using the consolidated framework for implementation research. Results During the 12-month implementation period, we conducted 23 stakeholder engagement activities with over 200 participants. We recruited 10 clinician champions representing nursing, anesthesia, and surgery. We formally interviewed 15 patients and 17 perioperative clinicians and identified key themes to include in an information campaign run as part of the implementation process. Two patient partners were engaged and advised on communications as well as grant and protocol development. Many anticipated and unanticipated challenges were encountered at all levels. Implementation was ultimately successful, with the Operating Room Black Box installed in August 2018, and data collection beginning shortly thereafter. Conclusions This paper represents the first step toward evidence-guided implementation of technologies for direct observation of performance for research and quality improvement in surgery. With technology increasingly being used in health care settings, the health care community should aim to optimize implementation processes in the best interest of health care professionals and patients.

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