Arie Regev

Outcome of Liver Transplantation for Drug- Induced Acute Liver Failure in the United States: Analysis of the United Network for Organ Sharing Database

Acute liver failure (ALF) is an uncommon but potentially lethal drug‐related adverse effect that often leads to liver transplantation (LT) or death. A retrospective cohort study was performed with the United Network for Organ Sharing Standard Transplant Analysis and Research files. Recipients who underwent LT for drug‐induced acute liver failure (DIALF) from 1987 through 2006 were analyzed. A total of 661 patients transplanted for DIALF were included in the analysis. The 4 leading implicated drug groups were acetaminophen (n = 265; 40%), antituberculosis drugs (n = 50; 8%), antiepileptics (n = 46; 7%), and antibiotics (n = 39; 6%). One‐year estimated survival probabilities were 76%, 82%, 52%, 82%, and 79% for acetaminophen, antituberculosis drugs, antiepileptics, antibiotics, and others, respectively. The lower rate of survival among those exposed to antiepileptics was observed mainly in children. Of the 22 patients less than 18 years old who had ALF due to antiepileptics, 73% died within the first year. The difference in overall survival between acetaminophen‐related and non–acetaminophen‐related ALF was not statistically significant. Patients with acetaminophen‐related ALF required dialysis prior to LT at a significantly higher rate than all other drug groups (27% versus 3%‐10%, P < 0.0001). According to Cox proportional hazards regression analysis, the independent pretransplant predictors of death after LT were being on life support, DIALF due to antiepileptic drugs at age less than 18, and elevated serum creatinine. In conclusion, the leading drug groups causing LT due to DIALF in the United States were acetaminophen, antituberculosis drugs, antiepileptics, and antibiotics. Children who had ALF due to antiepileptics had a substantially higher risk of death after LT in comparison with other drugs. Patients transplanted for acetaminophen‐related ALF required dialysis at a significantly higher rate. Being on life support, DIALF due to antiepileptics (at age less than 18), and elevated serum creatinine were independent pretransplant predictors of poor survival after LT for DIALF. Liver Transpl 15:719–729, 2009.

Hepatic Events Associated with Atomoxetine Treatment for Attention-Deficit Hyperactivity Disorder

AbstractObjective: This study describes and assesses potential hepatobiliary events related to atomoxetine therapy, as reported in clinical trials and as spontaneous adverse event reports post-launch in 2002. Methods: Case reports that contained potential hepatobiliary events were identified by a computerized search of the Eli Lilly and Company atomoxetine spontaneous adverse events and clinical trials databases. All cases were reviewed by at least two company physicians, one with expertise in hepatology, to determine the relevance of the information in respect of potential liver toxicity. Results: Of 7961 paediatric and adult patients treated with atomoxetine in clinical trials, 41 were identified as having hepatobiliary events requiring additional analysis. Most of these events were mild increases in ALT and AST levels. None of these cases met Hy’s rule criteria or progressed to liver failure. During the 4 years after market launch, 351 spontaneous reports of adverse events were related to the liver, of which 69 had other explanations unrelated to atomoxetine. Of the remaining 282 cases, 133 contained possible confounding factors (and were deemed to be possibly related), 146 presented too little information to assess, and three suggested atomoxetine as a probable cause of liver injuries. One of the three had a positive rechallenge. All three patients recovered after discontinuation of the drug. Conclusions: Since the launch of atomoxetine therapy, three spontaneously reported cases of reversible drug-induced liver injury were deemed probably related to it. Atomoxetine should be discontinued in patients with jaundice or laboratory evidence of liver injury and should not be restarted.

Drug-induced liver injury and drug development: industry perspective.

Despite intensive ongoing research, drug-induced live injury (DILI) remains a serious issue for care providers and patients, and has been a major cause of drug withdrawal and non-approval by regulatory authorities in the past 50 years. Consequently, DILI remains a major concern for the pharmaceutical industry and a leading cause for attrition during drug development. In most instances, severe DILI is an uncommon idiosyncratic reaction, which typically does not present during preclinical phases or early clinical phases of drug development. In the majority of cases, drugs that caused severe DILI in humans have not shown clear and consistent hepatotoxic signals in preclinical assessment including animal studies, cell cultures, or other methods. Despite intensive efforts to develop better biomarkers that would help in predicting DILI risk in earlier phases of drug development, such biomarkers are currently not supported by sufficient evidence and are not yet available for routine use by drug makers. Due to the lack of effective and accurate methods for prediction of idiosyncratic DILI during preclinical phases of drug development, different drug makers have adopted different approaches, which are often not supported by strong systematic evidence. Based on growing experience, it is becoming increasingly evident that milder forms of liver injury occurring during clinical development, when assessed correctly, may significantly enhance our ability to predict the drugs potential to cause more severe liver injury postmarketing. Strategies based on this concept have been adopted by many drug makers, and are being increasingly implemented during drug development. Meticulous causality assessment of individual hepatic cases and adherence to strict hepatic discontinuation rules are critical components of this approach and have to rely on thorough clinical evaluation and occasionally on assessment by liver experts experienced with DILI and drug development.

Gender disparity in liver transplant waiting‐list mortality: The importance of kidney function

Previous studies of men and women on the liver transplantation (LT) waiting list, without taking transplantation rates into account, have suggested a higher risk of mortality for women on the waiting list. The objective of this study was to compare men and women with respect to dying within 3 years of registration on the LT waiting list and to take into account both the immediate mortality risks and the transplantation rates. The analysis was based on Organ Procurement and Transplantation Network data for patients with end‐stage liver disease (ESLD) on the waiting list who were registered between February 2002 and August 2009. Competing risk survival analysis was performed to assess the gender disparity in waiting‐list mortality; 42,322 patients and 610,762 person‐months of waiting‐list experience were included in the analysis. The risk of dying within 3 years of listing was 19% and 17% in women and men, respectively (P < 0.0001). Among patients with kidney disease and especially those not on dialysis with an estimated glomerular filtration rate (eGFR) ≥15 and <30 mL/minute/1.73 m2, women had a substantially higher risk of dying on the waiting list within 3 years of registration versus men (26% versus 20%, P = 0.001). This disparity was related to lower transplantation rates in women (transplantation rate ratio = 0.68, P < 0.0001). Controlling for eGFR and other variables related to mortality risk, we found that the overall female‐male disparity disappeared. In conclusion, among patients with ESLD and kidney dysfunction who are not on dialysis, there is a substantial gender disparity in LT waiting‐list mortality. Our analysis suggests as an explanation the fact that women have lower transplantation rates than men in this group. The lower transplantation rates can be explained in part by the fact that Model for End‐Stage Liver Disease scores tend to be lower for women versus men because they are based on serum creatinine rather than the glomerular filtration rate. Liver Transpl 16:1147–1157, 2010.

Pharmacodynamic comparison of LY3023703, a novel microsomal prostaglandin e synthase 1 inhibitor, with celecoxib

To assess the safety, tolerability, and pharmacology of LY3023703, a microsomal prostaglandin E synthase 1 (mPGES1) inhibitor, a multiple ascending dose study was conducted. Forty‐eight subjects received LY3023703, celecoxib (400 mg), or placebo once daily for 28 days. Compared with placebo, LY3023703 inhibited ex vivo lipopolysaccharide‐stimulated prostaglandin E2 (PGE2) synthesis 91% and 97% on days 1 and 28, respectively, after 30‐mg dosing, comparable to celecoxibs effect (82% inhibition compared to placebo). Unlike celecoxib, which also inhibited prostacyclin synthesis by 44%, LY3023703 demonstrated a maximal increase in prostacyclin synthesis of 115%. Transient elevations of serum aminotransferase were observed in one subject after 30‐mg LY3023703 dosing (10× upper limit of normal (ULN)), and one subject after 15‐mg dosing (about 1.5× ULN). Results from this study suggest that mPGES1 inhibits inducible PGE synthesis without suppressing prostacyclin generation and presents a novel target for inflammatory pain.

Causality Assessment for Suspected DILI During Clinical Phases of Drug Development

Causality assessment is a critical step in establishing the diagnosis of drug induced liver injury (DILI) during drug development. DILI may resemble almost any type of liver disease, and often presents a serious challenge to clinical investigators and drug makers. The diagnosis of DILI is largely based upon a combination of a compatible clinical course, exclusion of all other reasonable causes, resemblance of clinical and pathological features to known features of liver injury due to the drug (i.e., “drug’s signature”), and incidence of liver injury among patients treated with the drug compared to placebo or comparator. Causality assessment for suspected DILI is currently performed using either evaluation by physicians with expertise in liver disorders (i.e., expert opinion) or standardized scoring instruments such as the Roussel Uclaf Causality Assessment Method (RUCAM). Both approaches are widely used in the post marketing setting. Causality assessment based on expert opinion is considered superior to standardized instruments such as RUCAM, in the setting of drug development, and is currently the preferred approach during clinical trials. There is a need for a systematic revision of RUCAM that will render it more suitable for the setting of clinical trials and drug development. Careful monitoring and meticulous data collection during clinical trials are essential in all cases with established liver injury to allow for a proper causality assessment. A workshop was convened to discuss best practices for the assessment of drug-induced liver injury (DILI) in clinical trials. This publication is based on the conclusions of this workshop.

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

Drugs that caused severe drug-induced live injury (DILI) in humans have typically not shown clear hepatotoxic signals in preclinical assessment. However, clinical trial databases may show evidence of a drugs potential for severe DILI if clinical and laboratory data are evaluated for evidence of milder liver injury. The most specific indicator during a clinical trial for a drugs potential to cause severe DILI is occurrence of cases of drug induced hepatocellular injury accompanied by altered liver function (eg, elevated direct bilirubin). Meticulous causality assessment of hepatic cases and strict adherence to hepatic discontinuation rules are critical components of this approach.

Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes

To evaluate whether treatment with LY2409021, a novel, selective glucagon receptor antagonist, is associated with changes in hepatic fat and other safety variables related to the benefit–risk profile for chronic use in patients with type 2 diabetes (T2D).

The Clinical Liver Safety Assessment Best Practices Workshop: Rationale, Goals, Accomplishments and the Future

The workshop was successful in bringing international experts from industry, academia, and regulatory agencies together to address the need for industry-wide standardization of liver safety data collection, causality assessment, and liver safety data management. It should be noted that the consensus statements contained in the manuscripts are simply that. They are not regulatory policy, but hopefully will stimulate progress toward the lengthy process of updating and revising the 2009 guidance document. There was near unanimous agreement that future guidelines and policies should be based as much as possible on data that should be available through precompetitive collaboration. Importantly, the workshop established a core international group of concerned experts from academia, industry and regulatory bodies to improve and standardize the approaches to assessing liver safety in clinical trials. An important goal to consider in this effort would be the establishment of a Liver Safety Research Consortium.

Drug-Induced Liver Injury: Morbidity, Mortality, and Hy’s Law

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 Drug-Induced Liver Injury: Morbidity, Mortality, and Hy’s Law 63 64 65 66 67 68 69 70 71 72 73 74 75 76 See “Use of Hy’s law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury,” by RoblesDiaz M, Lucena MI, Kaplowitz N, et al, on page 000; and “Idiosyncratic drug induced liver injury is associated with substantial morbidity and mortality within 6 months from onset, by Fontana RJ, Hayashi PH, Gu J, et al, on page 000.