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Recent years have seen the creation and popularization of various complex in vitro models (CIVMs), such as organoids and organs-on-chip, as a technology with the potential to reduce animal usage in pharma while also enhancing our ability to create safe and efficacious drugs for patients. Public awareness of CIVMs has increased, in part, due to the recent passage of the FDA Modernization Act 2.0. This visibility is expected to spur deeper investment in and adoption of such models. Thus, end-users and model developers alike require a framework to both understand the readiness of current models to enter the drug development process, and to assess upcoming models for the same. This review presents such a framework for model selection based on comparative -omics data (which we term model-omics), and metrics for qualification of specific test assays that a model may support that we term context-of-use (COU) assays. We surveyed existing healthy tissue models and assays for ten drug development-critical organs of the body, and provide evaluations of readiness and suggestions for improving model-omics and COU assays for each. In whole, this review comes from a pharma perspective, and seeks to provide an evaluation of where CIVMs are poised for maximum impact in the drug development process, and a roadmap for realizing that potential., (Creative Commons Attribution license.)

Sensory deprivation can lead to cross-modal cortical changes, whereby sensory brain regions deprived of input may be recruited to perform atypical function. Enhanced cross-modal responses to visual stimuli observed in auditory cortex of postlingually deaf cochlear implant (CI) users are hypothesized to reflect increased activation of cortical language regions, but it is unclear if this cross-modal activity is "adaptive" or "mal-adaptive" for speech understanding. To determine if increased activation of language regions is correlated with better speech understanding in CI users, we assessed task-related activation and functional connectivity of auditory and visual cortices to auditory and visual speech and non-speech stimuli in CI users (n = 14) and normal-hearing listeners (n = 17) and used functional near-infrared spectroscopy to measure hemodynamic responses. We used visually presented speech and non-speech to investigate neural processes related to linguistic content and observed that CI users show beneficial cross-modal effects. Specifically, an increase in connectivity between the left auditory and visual cortices-presumed primary sites of cortical language processing-was positively correlated with CI users' abilities to understand speech in background noise. Cross-modal activity in auditory cortex of postlingually deaf CI users may reflect adaptive activity of a distributed, multimodal speech network, recruited to enhance speech understanding., (© The Author(s) 2022. Published by Oxford University Press.)

Platinum-based chemotherapeutic agents cisplatin and carboplatin are widely used in cancer treatment worldwide and may result in ototoxic hearing loss. The high incidence of cancer and salient ototoxic effects of platinum-based compounds pose a global public health threat. The purpose of this study was twofold. First, to estimate the prevalence of ototoxic hearing loss associated with treatment with cisplatin and/or carboplatin via a systematic review and meta-analysis. Second, to estimate the annual global burden of ototoxic hearing loss associated with exposure to cisplatin and/or carboplatin. For the systematic review, three databases were searched (Ovid Medline, Ovid Embase, and Web of Science Core Collection) and studies that reported prevalence of objectively measured ototoxic hearing loss in cancer patients were included. A random effects meta-analysis determined pooled prevalence (95% confidence intervals [CI]) of ototoxic hearing loss overall, and estimates were stratified by treatment and patient attributes. Estimates of ototoxic hearing loss burden were created with published global estimates of incident cancers often treated with platinum-based compounds and cancer-specific treatment rates. Eighty-seven records (n = 5077 individuals) were included in the meta-analysis. Pooled prevalence of ototoxic hearing loss associated with cisplatin and/or carboplatin exposure was 43.17% [CI 37.93-48.56%]. Prevalence estimates were higher for regimens involving cisplatin (cisplatin only: 49.21% [CI 42.62-55.82%]; cisplatin & carboplatin: 56.05% [CI 45.12-66.43%]) versus carboplatin only (13.47% [CI 8.68-20.32%]). Our crude estimates of burden indicated approximately one million individuals worldwide are likely exposed to cisplatin and/or carboplatin, which would result in almost half a million cases of hearing loss per year, globally. There is an urgent need to reduce impacts of ototoxicity in cancer patients. This can be partially achieved by implementing existing strategies focused on primary, secondary, and tertiary hearing loss prevention. Primary ototoxicity prevention via otoprotectants should be a research and policy priority., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Drugs used in curative and prophylactic antimalarial treatment may be ototoxic and lead to permanent hearing loss, but there is no consensus regarding prevalence and permanence of ototoxic hearing loss caused by antimalarials. The purpose of this systematic narrative review was to synthesize current evidence on antimalarial ototoxicity in human populations., Method: Studies published between 2005 and 2018 that reported prevalence of post-treatment hearing loss in individuals treated for malaria were included., Results: Twenty-two studies including data from 21 countries were included. Primary themes of the included studies were to evaluate drug safety and/or efficacy (n = 13) or ototoxic effects of drugs (n = 9). Hearing data were measured objectively in 9 studies. Five studies focused on quinine (or derivates), 10 focused on artemisinin combination therapies, and 7 considered multiple drug combinations. There is a paucity of evidence that thoroughly reports potentially permanent ototoxic effects of antimalarials., Conclusions: Antimalarial drugs may be ototoxic in some cases. More research in human populations is needed to describe ototoxicity of current antimalarials and of future drugs that will be used/developed in response to antimalarial resistance. It is recommended that randomized trials evaluating drug safety objectively measure and report ototoxic hearing loss as an adverse event., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives estimate the prevalence of ototoxic hearing loss in drug-resistant tuberculosis (DR-TB) patients treated with aminoglycoside antibiotics via a systematic review and meta-analysis. Estimate the annual preventable cases of hearing loss in DR-TB patients and leverage findings to discuss primary, secondary and tertiary prevention. Methods studies published between 2005 and 2018 that reported prevalence of post-treatment hearing loss in DR-TB patients were included. We performed a random effects meta-analysis to determine pooled prevalence of ototoxic hearing loss overall and by medication type. Preventable hearing loss cases were estimated using World Health Organization (WHO) data on DR-TB treatment and prevalence determined by the meta-analysis. Results eighteen studies from 10 countries were included. Pooled prevalence of ototoxic hearing loss and the corresponding 95% confidence interval (CI) was 40.62% CI [32.77- 66.61%] for all drugs (kanamycin: 49.65% CI [32.77- 66.61%], amikacin: 38.93% CI [26.44-53.07%], capreomycin: 10.21% CI [4.33-22.21%]). Non-use of aminoglycosides may result in prevention of approximately 50,000 hearing loss cases annually. Conclusions aminoglycoside use results in high prevalence of ototoxic hearing loss. Widespread prevention of hearing loss can be achieved by following updated WHO guidelines for DR-TB treatment. When hearing loss cannot be avoided, secondary and tertiary prevention should be prioritized., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Unlabelled: Clinical evidence suggests that many cases of serious idiosyncratic drug-induced liver injury are mediated by the adaptive immune system in response to hepatic drug-protein adducts, also referred to as "drug-induced allergic hepatitis"; but detailed mechanistic proof has remained elusive due to the lack of animal models. We have hypothesized that drug-induced allergic hepatitis is as rare in animals as it is in humans due at least in part to the tolerogenic nature of the liver. We provide evidence that immune tolerance can be overcome in a murine model of halothane-induced liver injury initiated by trifluoroacetylated protein adducts of halothane formed in the liver. Twenty-four hours after female Balb/cJ mice were initially treated with halothane, perivenous necrosis and an infiltration of CD11b(+) Gr-1(high) cells were observed in the liver. Further study revealed a subpopulation of myeloid-derived suppressor cells within the CD11b(+) Gr-1(high) cell fraction that inhibited the proliferation of both CD4(+) and CD8(+) T cells. When CD11b(+) Gr-1(high) cells were depleted from the liver with Gr-1 antibody treatment, enhanced liver injury was observed at 9 days after halothane rechallenge. Toxicity was associated with increased serum levels of interleukin-4 and immunoglobulins G1 and E directed against hepatic trifluoroacetylated protein adducts, as well as increased hepatic infiltration of eosinophils and CD4(+) T cells, all features of an allergic reaction. When hepatic CD4(+) T cells were depleted 5 days after halothane rechallenge, trifluoroacetylated protein adduct-specific serum immunoglobulin and hepatotoxicity were reduced., Conclusion: Our data provide a rational approach for developing animal models of drug-induced allergic hepatitis mediated by the adaptive immune system and suggest that impaired liver tolerance may predispose patients to this disease., (© 2015 by the American Association for the Study of Liver Diseases. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Use of the fluoroquinolone antibiotic trovafloxacin (TVX) was restricted due to idiosyncratic, drug-induced liver injury (IDILI). Previous studies demonstrated that tumor necrosis factor-alpha (TNF) and TVX interact to cause death of hepatocytes in vitro that was associated with prolonged activation of c-Jun N-terminal kinase (JNK), activation of caspases 9 and 3, and DNA damage. The purpose of this study was to explore further the mechanism by which TVX interacts with TNF to cause cytotoxicity. Treatment with TVX caused cell cycle arrest, enhanced expression of p21 and impaired proliferation, but cell death only occurred after cotreatment with TVX and TNF. Cell death involved activation of extracellular signal-related kinase (ERK), which in turn activated caspase 3 and ataxia telangiectasia and Rad3-related (ATR), both of which contributed to cytotoxicity. Cotreatment of HepG2 cells with TVX and TNF caused double-strand breaks in DNA, and ERK contributed to this effect. Inhibition of caspase activity abolished the DNA strand breaks. The data suggest a complex interaction of TVX and TNF in which TVX causes replication stress, and the downstream effects are exacerbated by TNF, leading to hepatocellular death. These results raise the possibility that IDILI from TVX results from MAPK and ATR activation in hepatocytes initiated by interaction of cytokine signaling with drug-induced replication stress., (Copyright © 2015. Published by Elsevier Ireland Ltd.)