How to Avoid Being Surprised by Hepatotoxicity at the Final Stages of Drug Development and Approval

Regev, Arie

doi:10.1016/j.cld.2013.07.014

Cited by 22 publications

(16 citation statements)

References 44 publications

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“…In this context, potential safety issues on DILI should be recognized as early as possible during drug development in order to accurately predict the actual risk in the post-marketing phase [19] . There are currently a number of challenges and controversies in exploiting predictive preclinical studies, especially for animal models, where ethical issues pose important limitations [20] .…”

Section: Issues In Drug Developmentmentioning

confidence: 99%

“…Although some genetic associations (e.g., flucloxacillin and HLA-B 1 5701) have been identified, the clinical utility of genetic polymorphisms associated with drug-specific DILI appears still limited [1] . In addition, there are at least 3 groups of individuals showing different pattern of hepatic response: tolerates (the vast majority of patients without significant changes in liver biochemical tests), susceptibles (showing progressive increase in ALT level that continues to increase and evolves into clinically significant liver damage with signs and symptoms) and adaptors (showing transient increase in enzyme levels, which eventually return to baseline despite continuation of the drug) [19] . So far, regulatory authorities and drug developers have mainly relied on the so-called Hy's law or rule [22] , coined following Zimmerman's observations, to predict post-marketing risk of serious hepatic events and for making recommendations on whether treatment should be continued, stopped or its dose reduced, following biochemical abnormalities with the suspect drug.…”

Section: Issues In Drug Developmentmentioning

confidence: 99%

“…Given the importance of monitoring thousands of laboratory parameters during clinical phases, the eDISH method was developed to visualize, assess and summarize hepatic safety data during clinical trials [26] . As regards causality assessment, pharmaceutical companies prefer to rely on a 3-category scale instead of using the 5-category scale adopted by the DILIN consortium or the RUCAM score [19] .…”

Section: Issues In Drug Developmentmentioning

confidence: 99%

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Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database

Raschi¹,

Poluzzi²,

Koci³

et al. 2014

WJH

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AIM: To inform clinicians on the level of hepatotoxic risk among antimycotics in the post-marketing setting, following the marketing suspension of oral ketoconazole for drug-induced liver injury (DILI). METHODS:The publicly available international FAERS database (2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011) was used to extract DILI cases (including acute liver failure events), where antimycotics with systemic use or potential systemic absorption were reported as suspect or interacting agents. The reporting pattern was analyzed by calculating the reporting odds ratio and corresponding 95%CI, a measure of disproportionality, with time-trend analysis where appropriate. RESULTS:From 1687284 reports submitted over the 8-year period, 68115 regarded liver injury. Of these, 2.9% are related to antimycotics (1964 cases, of which 112 of acute liver failure). Eleven systemic antimycotics (including ketoconazole and the newer triazole derivatives voriconazole and posaconazole) and terbinafine (used systemically to treat onychomicosis) generated a significant disproportionality, indicating a post-marketing signal of risk. CONCLUSION:Virtually all antimycotics with systemic action or absorption are commonly reported in clinically significant cases of DILI. Clinicians must be aware of this aspect and monitor patients in case switch is considered, especially in critical poly-treated patients under chronic treatment.

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Section: Issues In Drug Developmentmentioning

confidence: 99%

Section: Issues In Drug Developmentmentioning

confidence: 99%

Section: Issues In Drug Developmentmentioning

confidence: 99%

See 1 more Smart Citation

Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database

Raschi¹,

Poluzzi²,

Koci³

et al. 2014

WJH

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“…Its annual incidence in the general population ranges between 14 and 19 events per 100,000 inhabitants with nearly 30% exhibiting jaundice (4, 5). It is one of the leading causes of acute liver failure in the United States (6, 7) and it continues to be an important barrier for new drug development and marketing (8). The Drug Induced Liver Injury Network (DILIN), funded by the U.S. National Institutes of Health, is a consortium of several academic institutions and its overarching goal is to comprehensively investigate all aspects of DILI in both children and adults (9).…”

Section: Introductionmentioning

confidence: 99%

Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study

Chalasani¹,

Fontana²,

Lee³

et al. 2015

Gastroenterology

703

751

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Background & Aims The drug-induced liver injury network (DILIN) is conducting a prospective study of patients with DILI in the United States. We present characteristics and subgroup analyses from the first 1257 patients enrolled in the study. Methods In an observational longitudinal study, we began collecting data on eligible individuals with suspected DILI in 2004, following them for 6 months or longer. Subjects were evaluated systematically for other etiologies, causes, and severity of DILI. Results Among 1257 enrolled subjects with suspected DILI, the causality was assessed in 1091 patients, and 899 were considered to have definite, highly likely, or probable DILI. Ten percent of patients died or underwent liver transplantation and 17% had chronic liver injury. In the 89 patients (10%) with pre-existing liver disease, DILI appeared to be more severe than in those without (difference not statistically significant; P=.09) and mortality was significantly higher (16% vs 5.2%; P<.001). Azithromycin was the implicated agent in a higher proportion of patients with pre-existing liver disease compared to those without liver disease (6.7% vs. 1.5%, p=0.006). Forty-one cases with latency ≤ 7 days were caused predominantly by antimicrobial agents (71%). Two most common causes for 60 DILI cases with latency >365 days were nitrofurantoin (25%) or minocycline (17%). There were no differences in outcomes of patients with short vs long latency of DILI. Compared to individuals younger than 65 y, individuals 65 y or older (n=149) were more likely to have cholestatic injury, although mortality and rate of liver transplantation did not differ. Nine patients (1%) had concomitant severe skin reactions; implicated agents were lamotrigine, azithromycin, carbamazepine, moxifloxacin, cephalexin, diclofenac, and nitrofurantoin. Four of these patients died. Conclusion Mortality from DILI is significantly higher in individuals with pre-existing liver disease or concomitant severe skin reactions compared to patients without. Further studies are needed to confirm the association between azithromycin and increased DILI in patients with chronic liver disease. Older age and short or long latencies are not associated with DILI mortality.

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“…Evidence for drug-induced hepatotoxicity leads to attrition during drug development, refusal of drug approval, and black box warning or postmarketing withdrawal (Regev, 2013). Druginduced hepatotoxicity can be intrinsic, the occurrence of which is relatively common, predictable, and dose-dependent (Russmann et al, 2009), or idiosyncratic, which occurs in a rare, unpredictable, and often dose-independent fashion in a few susceptible patients (Regev, 2013). Various mechanisms of drug-induced hepatotoxicity have been proposed, including formation of reactive electrophilic metabolites (Srivastava et al, 2010;Leung et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of In Situ Generated Valproyl 1-O-β-Acyl Glucuronide in Valproic Acid Toxicity in Sandwich-Cultured Rat Hepatocytes

2014

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Acyl glucuronides are reactive electrophilic metabolites implicated in the toxicity of carboxylic acid drugs. Valproyl 1-O-b-acyl glucuronide (VPA-G), which is a major metabolite of valproic acid (VPA), has been linked to the development of oxidative stress in VPA-treated rats. However, relatively little is known about the toxicity of in situ generated VPA-G and its contribution to VPA hepatotoxicity. Therefore, we investigated the effects of modulating the in situ formation of VPA-G on lactate dehydrogenase (LDH) release (a marker of necrosis), BODIPY 558/568 C 12 accumulation (a marker of steatosis), and cellular glutathione (GSH) content in VPA-treated sandwich-cultured rat hepatocytes. VPA increased LDH release and BODIPY 558/568 C 12 accumulation, whereas it had little or no effect on total GSH content. Among the various uridine 59-diphospho-glucuronosyltransferase inducers evaluated, b-naphthoflavone produced the greatest increase in VPA-G formation. This was accompanied by an attenuation of the increase in BODIPY 558/568 C 12 accumulation, but did not affect the change in LDH release or total GSH content in VPA-treated hepatocytes. Inhibition of in situ formation of VPA-G by borneol was not accompanied by substantive changes in the effects of VPA on any of the toxicity markers. In a comparative study, in situ generated diclofenac glucuronide was not toxic to rat hepatocytes, as assessed using the same chemical modulators, thereby demonstrating the utility of the sandwich-cultured rat hepatocyte model. Overall, in situ generated VPA-G was not toxic to sandwich-cultured rat hepatocytes, suggesting that VPA glucuronidation per se is not expected to be a contributing mechanism for VPA hepatotoxicity.

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How to Avoid Being Surprised by Hepatotoxicity at the Final Stages of Drug Development and Approval

Cited by 22 publications

References 44 publications

Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database

Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database

Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study

Evaluation of In Situ Generated Valproyl 1-O-β-Acyl Glucuronide in Valproic Acid Toxicity in Sandwich-Cultured Rat Hepatocytes

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