Interpretation, Integration, and Implementation of In Vitro Assay Data: The Predictive Toxicity Challenge

Light, Deborah S.; Aleo, Michael D.; Kenna, J. Gerry

doi:10.1007/978-1-4939-7677-5_17

Cited by 5 publications

(5 citation statements)

References 47 publications

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“…Despite the fact that idiosyncratic DILI occurs in a very small proportion of exposed patients, screening for stress in cell systems and isolated mitochondria is predictive of the risk associated with a large proportion of the drugs known to cause idiosyncratic DILI. 3,4 The key feature of idiosyncratic DILI with most drugs is the critical role of the adaptive immune system. Many drugs which cause immunemediated idiosyncratic DILI exhibit no systemic allergic features such as rash and eosinophilia.…”

Section: Introductionmentioning

confidence: 99%

EASL Clinical Practice Guidelines: Drug-induced liver injury

Andrade¹,

Aithal²,

Bjõrnsson³

et al. 2019

Journal of Hepatology

666

394

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Idiosyncratic (unpredictable) drug-induced liver injury is one of the most challenging liver disorders faced by hepatologists, because of the myriad of drugs used in clinical practice, available herbs and dietary supplements with hepatotoxic potential, the ability of the condition to present with a variety of clinical and pathological phenotypes and the current absence of specific biomarkers. This makes the diagnosis of drug-induced liver injury an uncertain process, requiring a high degree of awareness of the condition and the careful exclusion of alternative aetiologies of liver disease. Idiosyncratic hepatotoxicity can be severe, leading to a particularly serious variety of acute liver failure for which no effective therapy has yet been developed. These Clinical Practice Guidelines summarize the available evidence on risk factors, diagnosis, management and risk minimization strategies for drug-induced liver jury.

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Section: Introductionmentioning

confidence: 99%

EASL Clinical Practice Guidelines: Drug-induced liver injury

Andrade¹,

Aithal²,

Bjõrnsson³

et al. 2019

Journal of Hepatology

666

394

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“…Decision-making is company centric, and this approach should not be construed as an alternative to clinical trials to understand the balance of efficacy versus hepatic safety. Adoption and implementation of novel multipronged approaches like this can present internal challenges . It is noted that many patients derive therapeutic benefit using drugs with Most-DILI-concern potential without personal safety being compromised.…”

Section: Discussionmentioning

confidence: 99%

“…Adoption and implementation of novel multipronged approaches like this can present internal challenges. 108 It is noted that many patients derive therapeutic benefit using drugs with Most-DILI-concern potential without personal safety being compromised. Precision medicine approaches may help identify patients with increased sensitivity to liver injury based on compound activity in these and other mechanistic assays relevant to driving severe liver injury.…”

Section: ■ Discussionmentioning

confidence: 99%

Moving beyond Binary Predictions of Human Drug-Induced Liver Injury (DILI) toward Contrasting Relative Risk Potential

Aleo¹,

Shah²,

Allen

et al. 2019

Chem. Res. Toxicol.

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The hepatic risk matrix (HRM) was developed and used to differentiate lead clinical and back-up drug candidates against competitor/ marketed drugs within the same pharmaceutical class for their potential to cause human drug-induced liver injury (DILI). The hybrid HRM scoring system blends physicochemical properties (Rule of Two Model: dose and lipophilicity or Partition Model: dose, ionization state, lipophilicity, and fractional carbon bond saturation) with common toxicity mechanisms (cytotoxicity, mitochondrial dysfunction, and bile salt export pump (BSEP) inhibition) that promote DILI. HRM scores are based on bracketed safety margins (<1, 1−10, 10−100, and >100× clinical C max,total ). On the basis of well-established clinical safety experience of marketed/withdrawn drug candidates, the background analysis consists of 200 drugs from the Liver Toxicity Knowledge Base annotated as Most-DILI-(79), Less-DILI-(56), No-DILI-(47), and Ambiguous-DILI-concern (18) drugs. Scores were generated for over 21 internal and 7 external drug candidates discontinued for unacceptable incidence/magnitude of liver transaminase elevations during clinical trials or withdrawn for liver injury severity. Both hybrid scoring systems identified 70−80% Most-DILI-concern drugs, but more importantly, stratified successful/unsuccessful drug candidates for liver safety (incidence/severity of transaminase elevations and approved drug labels). Incorporating other mechanisms (reactive metabolite and cytotoxic metabolite generation and hepatic efflux transport inhibition, other than BSEP) to the HRM had minimal beneficial impact in DILI prediction/stratification. As is, the hybrid scoring system was positioned for portfolio assessments to contrast DILI risk potential of small molecule drug candidates in early clinical development. This stratified approach for DILI prediction aided decisions regarding drug candidate progression, follow-up mechanistic work, back-up selection, clinical dose selection, and due diligence assessments in favor of compounds with less implied clinical hepatotoxicity risk.

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“…Alternatively, in some instances a drug or metabolite may alter the HLA binding groove leading to misdirected peptide presentation. A potential unifying aspect of both intrinsic and idiosyncratic DILI has been demonstrated using in vitro systems 74 . Using these test systems to identify toxic stress in the absence of innate or adaptive immune system may suggest that hepatocyte stress promotes neoantigen formation upstream of immunity and/or generates signals that co-activate the immune response.…”

Section: [H1] Mechanisms/pathophysiology [H2] Normal Drug Metabolism and Transportmentioning

confidence: 99%