Drug‐induced liver injury (DILI) is a major public health problem. Intrinsic (dose‐dependent) DILI associated with acetaminophen overdose is the number one cause of acute liver failure in the US. ...However, the most problematic type of DILI impacting drug development is idiosyncratic, occurring only very rarely among treated patients and often only after several weeks or months of treatment with the offending drug. Recent advances in our understanding of the pathogenesis of DILI suggest that three mechanisms may underlie most hepatocyte effects in response to both intrinsic and idiosyncratic DILI drugs: mitochondrial dysfunction, oxidative stress, and alterations in bile acid homeostasis. However, in some cases hepatocyte stress promotes an immune response that results in clinically important idiosyncratic DILI. This review discusses recent advances in our understanding of the pathogenesis of both intrinsic and idiosyncratic DILI as well as emerging tools and techniques that will likely improve DILI risk identification and management.
Drug‐induced liver injury (DILI) is the most frequent reason cited for the withdrawal of approved drugs from the market and accounts for up to 15% of the cases of acute liver failure. Investigators ...around the globe have begun to identify and study patients with DILI; several large registries and tissue banks are being established. In order to gain the maximum scientific benefit from these efforts, the definitions and terminology related to the clinical phenotypes of DILI must be harmonized. For this purpose, an international DILI Expert Working Group of clinicians and scientists reviewed current DILI terminology and diagnostic criteria so as to develop more uniform criteria that would define and characterize the spectrum of clinical syndromes that constitute DILI. Consensus was established with respect to the threshold criteria for definition of a case as being DILI, the pattern of liver injury, causality assessment, severity, and chronicity. Consensus was also reached on approaches to characterizing DILI in the setting of chronic liver diseases, including autoimmune hepatitis (AIH).
Clinical Pharmacology & Therapeutics (2011) 89 6, 806–815. doi:10.1038/clpt.2011.58
During a recent review of a new drug application for treatment of a chronic disease, US Food and Drug Administration (FDA) regulators agreed with the sponsor's assessment of efficacy. However, it was ...noted that two subjects receiving active treatment experienced abnormal liver chemistries that possibly, but not definitely, indicated a liver safety liability. The sponsor was told that a prerequisite for approval would be a new clinical trial involving 20,000 patients treated for 1 year, with 10,000 receiving the new drug and 10,000 receiving a comparator treatment. The sponsor is now faced with the substantial costs involved in undertaking such a large study, the loss of patent life during the conduct and analysis of the study, and the prospect of losing in‐class market position. If the drug is ultimately approved, this detour will result in costs and potential revenue loss to the sponsor of well over $1 billion.
Clinical Pharmacology & Therapeutics (2011) 89 6, 788–790. doi:10.1038/clpt.2011.63
Achieving the ability to identify individuals who are susceptible to drug‐induced liver injury (DILI) would represent a major advance in personalized medicine. Clayton et al. demonstrated that the ...pattern of endogenous metabolites in urine could predict susceptibility to acetaminophen‐induced liver injury in rats. We designed a clinical study to test this approach in healthy adults who received 4 g of acetaminophen per day for 7 days. Urine metabolite profiles obtained before the start of treatment were not sufficient to distinguish which of the subjects would develop mild liver injury, as indicated by a rise in alanine aminotransferase (ALT) to a level more than twice the baseline value (responders). However, profiles obtained shortly after the start of treatment, but prior to ALT elevation, could distinguish responders from nonresponders. Statistical analyses revealed that predictive metabolites included those derived from the toxic metabolite N‐acetyl paraquinone imine (NAPQI), but that the inclusion of endogenous metabolites was required for significant prediction. This “early‐intervention pharmaco‐metabonomics” approach should now be tested in clinical trials of other potentially hepatotoxic drugs.
Clinical Pharmacology & Therapeutics (2010) 88 1, 45–51. doi: 10.1038/clpt.2009.240
Background & Aims The Drug-Induced Liver Injury Network 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 with those without liver disease (6.7% vs 1.5%; P = .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 with individuals younger than 65 years, individuals 65 years 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. Conclusions Mortality from DILI is significantly higher in individuals with pre-existing liver disease or concomitant severe skin reactions compared with patients without. Additional 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.
The occurrence of drug‐induced liver injury (DILI) presents a significant safety issue for patients and represents a major cause of regulatory action. The methods that are in current use for early ...detection and prediction of DILI in patients are not adequate. The liver is the major site of synthesis of endogenous metabolites, and data suggest that alterations in the profiles of endogenous metabolites (“the metabolome”) may precede development of clinically overt DILI. Metabonomics involves the application of analytical technologies such as nuclear magnetic resonance and mass spectrometry to detect changes in the metabolome. In this review, we describe the emerging role of metabonomics in predicting and understanding the mechanisms underlying DILI. Recent human clinical trials of drugs, including acetaminophen (APAP) and ximelagatran, have shown that the metabonomics of biofluids (plasma and urine) collected before and immediately after dosing can identify individual patients who are likely to develop DILI. These studies support the need to include metabonomic investigations in clinical trials of potentially hepatotoxic medications.
Clinical Pharmacology & Therapeutics (2010) 88 3, 394–399. doi: 10.1038/clpt.2010.151
Heparins have been reported to cause elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) but have not been associated with clinically significant liver injury. The ...mechanisms underlying these benign laboratory abnormalities are unknown. Forty‐eight healthy men were randomized to receive subcutaneous injections of unfractionated heparin (UFH; 150 U/kg), enoxaparin sodium (1 mg/kg), dalteparin sodium (120 IU/kg), or adomiparin sodium (125 IU/kg; a novel heparin) every 12 h for 4.5 days. Asymptomatic elevations in serum ALT or AST were observed in >90% of the subjects. Elevations were also observed in the levels of serum sorbitol dehydrogenase (SDH), glutamate dehydrogenase (GLDH), miR‐122, high‐mobility group box‐1 protein (including the acetylated form), full‐length keratin 18, and DNA. Keratin 18 fragments, which are apoptosis biomarkers, were not detected. Biomarker profiles did not differ significantly across heparin treatments. We conclude that heparins as a class cause self‐limited and mild hepatocyte necrosis with secondary activation of an innate immune response.
Clinical Pharmacology & Therapeutics (2012); 92 2, 214–220. doi:10.1038/clpt.2012.40
Many seabirds are killed or injured by fishing gear, contributing to the high proportion of threatened seabirds. This study estimates the impact of the South African deep-water hake Merluccius spp. ...trawl fishery on seabirds. At least 30 birds were killed in 190 h of dedicated observations of trawl warps during 2004 and 2005. Most were killed when their wings were entangled around the trawl warp and they were dragged under by the force of the water passing over the warp. Albatrosses were killed most frequently: shy albatrosses Thalassarche cauta (43% of all birds killed) and black-browed albatrosses Thalassarche melanophrys (37%), with smaller numbers of white-chinned petrels Procellaria aequinoctialis (10%), Cape gannets Morus capensis (7%) and sooty shearwaters Puffinus griseus (3%). Mortalities occurred mainly during dumping of fishery wastes, and were more frequent in winter, when more birds attended fishing vessels. Average mortality rates were 0.56 (95% confidence interval 0.32-0.82) birds killed per hour during dumping in winter, 0.21 (0.07-0.38) during dumping in summer and 0.09 (0.02-0.19) when not dumping in winter. No birds were killed in the absence of dumping in summer. Albatrosses suffered a disproportionately high mortality rate, with 15% of birds dragged under drowning, compared with 4% of all other species. Deaths resulting from entanglement in fishing nets mainly affected Cape gannets M. capensis, and occurred at an average rate of 3.0 (0.9-5.4) birds per 100 trawls (n=331 trawls). Serious warp incidents were independent of age among albatrosses, but there was a tendency for immature gannets to have a higher interaction rate than adults. Crude extrapolation suggests that total mortality is c. 18 000 (8000-31 000) birds per year, of which 85% are killed on warps and 15% entangled in nets. These estimates are of the same order of magnitude as estimates of long-line bycatch in South African waters. Mitigation measures have been implemented to reduce mortality in this fishery.
Troglitazone (TGZ) causes delayed, life‐threatening drug‐induced liver injury in some patients but was not hepatotoxic in rats. This study investigated altered bile acid homeostasis as a mechanism of ...TGZ hepatotoxicity using a systems pharmacology model incorporating drug/metabolite disposition, bile acid physiology/pathophysiology, hepatocyte life cycle, and liver injury biomarkers. In the simulated human population, TGZ (200–600 mg/day × 6 months) resulted in delayed increases in serum alanine transaminase >3× the upper limit of normal in 0.3–5.1%, with concomitant bilirubin elevations >2× the upper limit of normal in 0.3–3.6%, of the population. By contrast, pioglitazone (15–45 mg/day × 6 months) did not elicit hepatotoxicity, consistent with clinical data. TGZ was not hepatotoxic in the simulated rat population. In summary, mechanistic modeling based only on bile acid effects accurately predicted the incidence, delayed presentation, and species differences in TGZ hepatotoxicity, in addition to predicting the relative liver safety of pioglitazone. Systems pharmacology models integrating physiology and experimental data can evaluate drug‐induced liver injury mechanisms and may be useful to predict the hepatotoxic potential of drug candidates.
Clinical Pharmacology & Therapeutics (2014); 96 5, 589–598. doi:10.1038/clpt.2014.158
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