The influence of drug properties and host factors on delayed onset of symptoms in drug‐induced liver injury

González-Jiménez, A.; McEuen, Kristin; Chen, Minjun; Suzuki, Ayako; Robles‐Díaz, Mercedes; Medina‐Cáliz, Inmaculada; Bessone, Fernando; Hernández, Nelia; Arrese, Marco; Paraná, Raymundo; Lucena, M. Isabel; Stephens, Camilla; Andrade, Raúl J.

doi:10.1111/liv.13952

Cited by 11 publications

(9 citation statements)

References 23 publications

(40 reference statements)

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“…In addition, some of these studies considered elevated liver biochemistries at 6 months as chronic or persistent DILI; others considered that time to be at 12 months. Besides clinical factors, drug factors such as lipophilicity, dose, and metabolism can also influence DILI phenotypes 30,31 or DILI risk. 13,15,32,33 In this study, we found that the extent of hepatic metabolism of offending drugs was significantly associated with recovery time.…”

Section: Discussionmentioning

confidence: 99%

Elevated bilirubin, alkaline phosphatase at onset, and drug metabolism are associated with prolonged recovery from DILI

Ashby

Zhuang

González-Jiménez

et al. 2021

Journal of Hepatology

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Accelerated failure time analysis of clinical factors and drug properties Spanish DILI Cohort (N = 257) LiverTox Cohort (N = 191) Development of recovery score model External validations Score = 0.227× log e (ALP) + 0.277 × log e (Bilirubin) + 0.161 × log e (Onset) -0.440 × extent of metabolism iDILIC cohort (N = 294) Highlights Bilirubin, ALP, time to onset, and drug metabolism influence DILI recovery time. Parametric time-to-event method identifies risk factors for prolonged DILI recovery. Recovery score model predicts the trajectory of DILI recovery for individual patients.

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Section: Discussionmentioning

confidence: 99%

Elevated bilirubin, alkaline phosphatase at onset, and drug metabolism are associated with prolonged recovery from DILI

Ashby

Zhuang

González-Jiménez

et al. 2021

Journal of Hepatology

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“…According to a previous study, the incidence of DILI is approximately 2.7 cases of DILI per 100 000 adults, and because the prevalence of DILI is quite low, the sample size was insufficient to determine the frequency of DILI development in a clinical trial . Furthermore, the universal risk factor for DILI remains unclear, although genetic risk might be associated with DILI . Several studies suggested that the pathophysiology of DILI might be multifactorial; thus, establishing an examination with high sensitivity for prediction of idiosyncratic DILI is difficult .…”

Section: Discussionmentioning

confidence: 99%

Unfavorable prognosis of patients with acute liver injury due to drug‐induced liver injury and acute exacerbation of hepatitis B virus infection

Kakisaka

Suzuki

Jinnouchi

et al. 2019

Hepatology Research

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Aim Acute liver injury (ALI) has a favorable prognosis, whereas acute liver failure (ALF) leads to organ failure and thus has an unfavorable prognosis. The effect of each etiology on the clinical course of ALI remains unclear. This study aimed to determine how each etiology and glucocorticoid on the unfavorable etiology affects the clinical course of ALI. Methods This prospective observational study enrolled 522 patients with ALI/ALF from 2004 and 2017. To evaluate the influence of etiology on prognosis, decision tree analysis was carried out using age, disease type, etiology, and the presence of hepatic encephalopathy. Results Of 522 patients, 398 patients satisfied the ALI criteria at registration in this study. The ALI etiologies were as follows: viral hepatitis through oral infection (n = 54), acute hepatitis B virus (HBV) infection (n = 24), acute exacerbation of HBV infection (n = 30), de novo hepatitis due to HBV (n = 5), autoimmune hepatitis (n = 59), drug‐induced liver injury (DILI; n = 85), other viruses (n = 12), and undetermined (n = 129). ALI in 46 patients progressed to ALF after registration. Of 11 patients (age >52 years) with ALF due to acute exacerbation of HBV infection or DILI, seven patients (63.6%) died. Whether glucocorticoid affected the clinical course of ALI due to acute exacerbation of HBV infection or DILI was evaluated using propensity score matching (age, sex, alanine aminotransferase, total bilirubin, and prothrombin time‐international normalized ratio). Glucocorticoid did not improve the prognosis of ALI patients due to the two etiologies. Conclusions Progression of ALI due to DILI or acute exacerbation of HBV infection to ALF showed a poor prognosis.

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“…Notably, the threshold dose may have substantial inter-individual variability (DILI may occur when increasing the dose, still within the recommended daily dose range) (Carrascosa et al, 2015), and DILI induced by agents used at daily dose higher than 50 mg was found to have significantly shorter latency period as compared with DILI caused by drugs taken at lower dosage (38 vs 56 days) (Vuppalanchi et al, 2014). Antibiotics are an exception: amoxicillin-clavulanate (daily dose >1000 mg) was associated with a particular phenotype of “delayed onset of DILI,” a term referring to the delay in DILI manifestations after interruption of the agent, to be distinguished from long latency time during drug administration (Gonzalez-Jimenez et al, 2019). Therefore, the question arises as to whether or not high dose is just an epiphenomenon, and DILI simply overlaps with most frequently prescribed medications used at recommended doses.…”

Section: Etiology Of Dili: the Role Of Drug Propertiesmentioning

confidence: 99%

Strategies for Early Prediction and Timely Recognition of Drug-Induced Liver Injury: The Case of Cyclin-Dependent Kinase 4/6 Inhibitors

Raschi

Ponti

2019

Front. Pharmacol.

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The idiosyncratic nature of drug-induced liver injury (DILI) represents a current challenge for drug developers, regulators and clinicians. The myriad of agents (including medications, herbals, and dietary supplements) with recognized DILI potential not only strengthens the importance of the post-marketing phase, when urgent withdrawal sometimes occurs for rare unanticipated liver toxicity, but also shows the imperfect predictivity of pre-clinical models and the lack of validated biomarkers beyond traditional, non-specific liver function tests. After briefly reviewing proposed key mechanisms of DILI, we will focus on drug-related risk factors (physiochemical and pharmacokinetic properties) recently proposed as predictors of DILI and use cyclin-dependent kinase 4/6 inhibitors, relatively novel oral anticancer medications approved for breast cancer, as a case study to discuss the feasibility of early detection of DILI signals during drug development: published data from pivotal clinical trials, unpublished post-marketing reports of liver adverse events, and pharmacokinetic properties will be used to provide a comparative evaluation of their liver safety and gain insight into drug-related risk factors likely to explain the observed differences.

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The influence of drug properties and host factors on delayed onset of symptoms in drug‐induced liver injury

Abstract: This study demonstrated that delayed onset, a specific DILI phenotype, is explained by complex interactions among drug properties and host factors and provided mechanistic hypotheses for future studies. These findings can help improve the diagnostic capability and causality assessment.

Cited by 11 publications

References 23 publications

Elevated bilirubin, alkaline phosphatase at onset, and drug metabolism are associated with prolonged recovery from DILI

Elevated bilirubin, alkaline phosphatase at onset, and drug metabolism are associated with prolonged recovery from DILI

Unfavorable prognosis of patients with acute liver injury due to drug‐induced liver injury and acute exacerbation of hepatitis B virus infection

Strategies for Early Prediction and Timely Recognition of Drug-Induced Liver Injury: The Case of Cyclin-Dependent Kinase 4/6 Inhibitors

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