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European Biopharmaceutical Review

Mindful Medical Monitoring

Drug induced liver injury is one of the most common causes of safety-related drug market withdrawals.Early and correct identifi cation is key, and careful
consideration of liver function test results can avoid the mistaken diagnoses that prove costly to a trial.

When considering the safety issues that can lead to the termination of drug development, failure in obtaining regulatory approval, and withdrawal or use restrictions of existing drugs on the market, drug induced liver injury (DILI) remains the most common cause
(1,3). DILI is also diffi cult to predict. In a review of 150 investigational drugs, the concordance between animal and human fi ndings were only 55 per cent – a sharp contrast to the much higher concordance of other targets such as the haematological (91 per cent), gastrointestinal (85 per cent) and cardiovascular (80 per cent) systems (2).

Medicines can cause DILI through a variety of mechanisms (3). An index of suspicion is necessary to establish the diagnosis expeditiously. Though severe
cases of DILI are relatively rare – one in 10,000 to one in 100,000 treated
patients – it is a frequent cause of acute liver failure (ALF), up to 13 per cent of all ALF cases in some studies (4-6). In view of the impact of DILI on the public,
regulators encourage drug developers to gather all pertinent information, assess time courses of liver test abnormalities and evaluate each patient for alternative causes of liver injury to avoid hyper diagnostic cases of DILI (7). This article presents three cases where study drugs were initially suspected as the cause for DILI. In these cases no relationship with the study drug was confi rmed.
Case Reports

Case One

A 68 year-old female with acute myeloid leukemia (AML) entered a clinical trial to receive either a novel antibody or placebo. Concomitant
medications included ranitidine, nimesulide and clemastine. Baseline liver function tests (LFTs) were normal. She received a fi rst dose of the study drug without any complications noted, followed by a second infusion a week later. After the second infusion, the patient developed a fever and minimal jaundice. Her LFTs increased: alkaline phosphatase (ALP) levels rose to 555U/L (normal range 40-140U/L), alasine transaminase (ALAT) levels rose to 137U/L (normal range 5-45U/L), and aspartate transaminase (ASAT) levels rose to 53U/L evaluation revealed leukemic infiltration of the liver. Progression of AML was diagnosed and leukemic infiltration was identified as the cause of elevated LFTs. Administration of the study drug was restored. LFTs were monitored and the enzymes normalised in a month, demonstrating that, in this case, administration of the study drug was not the cause of the liver disorder.

Case Two

 A 64 year-old female with a medical history of asthma entered a clinical trial to receive an antibiotic (a novel dihydrofolate reductase inhibitor) for an infected foot ulcer. Concomitant medications included formoterol and lormetazepam. The treatment was effective and no adverse events (AEs) were noted. Nine days after the final administration of the study drug, the patient developed elevated liver enzymes with ALAT levels of 226U/L (normal range 1-30U/L) and ASAT levels of 98U/L (normal range 1-32U/L). ALP levels and total bilirubin (TB) were normal. Serology tests for hepatitis B and C were negative. The LFTs returned to a normal range four days later, and the elevation of liver enzymes was initially considered to be related to the study drug by the investigator. Administration of the study drug was terminated. From a study design viewpoint, the patient was classified as a treatment failure; but considering co-morbidities and concomitant medications, the medical monitor recommended further surveillance of LFTs. These revealed a recurrence in increased liver enzymes, reaching a three- to four-fold increase after three weeks, while the period of the study drug’s half-life did not exceed 16 hours. Even though a definite etiology of the increased levels was not identified, the investigator reassessed the increase of liver enzymes as likely to be related to concomitant therapy rather than to the study drug.

Case Three

A 24 year-old female with diabetes mellitus (DM) entered a clinical trial for an anti-diabetic drug six months before developing a urinary tract infection caused by Escherichia coli, and received ciprofloxacin for 10 days for its treatment. Concomitant medications included NPH and regular insulin. The patient had normal LFTs before the start of ciprofloxacin intake. One day after the completion of oral ciprofloxacin, the patient presented with elevated ASAT levels of 927U/L (normal range 0-45U/L) and ALAT levels of 788U/L (normal range 0-55U/ L) with no relevant clinical symptoms. TB and ALP levels were normal, and HBV, HCV, and CMV serology was negative. Abdominal ultrasound results were also unremarkable. The physician assessed DILI as related to the study medication, though the patient had received the study drug for a rather long time (about six months) without a recent dosage increase of the study drug, and no LFTs changes had been observed before the urinary tract infection and administration of ciprofloxacin. The patient was withdrawn from the study and liver enzymes remained elevated for one and a half months before returning to normal levels. The medical monitor and investigator discussed this occurrence at length, and the investigator subsequently agreed that an increase in LFTs was unlikely to be related to the study medication, and was more likely to be related to the administration of ciprofloxacin.

Detecting DILI

Severe DILI leading to liver failure, transplantation or death is a relatively rare event (6). Monitoring of LFTs is routine in clinical trials, and occasional elevations do not usually lead to patients’ discontinuation or cessation of the drug testing. Nevertheless, any increase of liver enzymes is a key indicator. Frequently, severe DILI is identified after the drug enters the market. In recent years, the FDA removed two drugs from the market due to their hepatotoxicity: bromfenac and troglitazone. In April 2010, the FDA required a black box warning to be issued, prescribing information to propylthiouracil emphasising the risk of severe and, in several cases fatal, liver injury (7).

DILI is also generally difficult to detect as it is not predictable or clearly dose-related, but rather depends on individual susceptibilities that have yet to be characterised. A typical application for marketing authorisation contains information of exposure in 1,000-3,000 patients, and applications for biologics frequently include even fewer patients due to the fact that severe DILI is rarely registered in drug development (3). Thus any single case of significant transaminase elevation during a clinical trial should be handled with close attention.

The major mechanisms of DILI are hepatocellular, cholestatic, and a mix of the two (6). Predominantly severe DILI constitutes hepatocellular injury, which demonstrates a rapid increase of liver enzymes in the serum due to its release from injured hepatocytes. One of the diagnostic cornerstones for DILI is whether or not a reasonable temporal association with a suspected medicine was observed. Diagnosing DILI is based on Hy’s Law and consists of three components (6):

  • The drug causes hepatocellular injury, generally indicated by a higher incidence of three-fold, or greater elevations above the upper limit of normal of ALAT or ASAT levels, than the ‘safe’ control 
  • Among patients showing such LFTs elevations, one or more also show elevation of serum TB two times greater than the upper normal limit, without cholestasis (increase of ALP)
  • No other reason can explain the combination of increased aminotransferase and TB, including viral hepatitis A, B or C, a preexisting or acute liver disease, or another drug capable of causing the observed injury

In clinical trials, fi nding a single case that exhibits all components of Hy’s Law is considered ominous, and fi nding two cases is highly predictive of a potential for severe DILI. Although a temporal sequence appears to be integral to causality, the logical fallacy of assuming causality may contribute to misdiagnosis of DILI in clinical trials. In all three cases presented, LFTs elevation occurred after the administration of the study drug and DILI was initially suspected by investigators to be related to the study drug, although in all cases DILI was ultimately considered to be unrelated.

In Case One (AML), a liver biopsy excluded DILI and diagnosed AML progression. In Case Two (infected ulcer), repeated elevation of liver enzymes in the absence of reexposure made the study drug an unlikely culprit. In Case Three (DM), the tests were characteristic of hepatocellular injury. The temporal association between elevated LFTs and the start of ciprofloxacin, the defervescence after stopping it, the course of the reaction, and the known association of abnormal LFTs with flouroquinolones supports the assessment of the liver injury in this case as probably related to fluoroquinolone, according to the Roussel Uclaf Causality Assessment Method (RUCAM) scale (8,9).


It is important to analyse each case of elevated LFTs levels, consider all alternative etiologies for liver injury, and assess its causality. Medical monitors must consult with investigators regarding all possible factors that may cause elevated LFTs levels and suggest follow-up actions that may confirm or redirect the investigator’s opinion. Only investigators have the right to make clinical decisions in a trial; however, medical monitors should communicate with investigators in each case to ensure the information necessary for an accurate diagnosis is available. In difficult and challenging cases,a liver biopsy may help make the correct diagnosis.


 1. Lee WM and Senior JR, Recognizing drug induced liver injury: current problems, possible solutions, Toxicol Pathol 33: p155, 2005
 2. Olson H et al, Concordance of the toxicity of pharmaceuticals in humans and in animals, Regul Toxicol Pharmacol 32(1): pp56-67, 2000
 3. Chang CY and Schiano TD, Review article: drug hepatotoxicity, Aliment Pharmacol Ther 25(10): p1,135, 2007
 4. Bell LN and Chalasani N, Epidemiology of idiosyncratic drug-induced liver injury, Semin Liver Dis 29(4): p337, 2009
 5. Ostapowicz G, Fontana RJ, Schiødt FV et al, U.S. Acute Liver Failure Study Group. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States, Ann Intern Med 137(12): pp947-954, 2002
 6. Abboud G and Kaplowitz N, Druginduced liver injury, Drug Saf 30(4): pp277-294, 2007
 7. FDA Guidance for industry, Druginduced liver injury: premarketing clinical evaluation, July 2009
 8. Orman ES et al, Clinical and histopathologic features of fluoroquinolone-induced liver injury, Clin Gastroenterol Hepatol 9(6): pp517-523, 2011   
 9. Lewis JH, Larrey D, Olsson R, Lee WM, Frison L and Keisu M, Utility of the Roussel Uclaf Causality Assessment Method (RUCAM) to analyze the    hepatic findings in a clinical trial program: evaluation of the direct thrombin inhibitor ximelagatran, Int J Clin Pharmacol Ther 46(7): pp327-339, 2008

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Akhil Kumar is a Medical Director at PSI CRO AG. Prior to joining PSI, he worked for MGI Pharma as a Medical Director and as an Independent Consultant. He is board certifi ed in both Medical Oncology and Hematology in the US, and Assistant Professor of Medical Oncology. Akhil is a member of ASCO and ASH and he author of 11 publications.

Maxim Kosov is the Medical Affairs Manager at PSI CRO AG, and is a board-certifi ed physician in neonatology. Before joining PSI he worked at the Ott Research Institute of Obstetrics & Gynecology and Pediatric Medical Academy. Maxim has published 28 articles.

Marcelo Yantorno MD has been working as a Medical Offi cer at PSI CRO AG since 2008. He has board certifi cation in Internal Medicine and is co-author of 13 publications. Before joining PSI, Marcelo worked as an attending physician and has participated as sub-investigator in more than 30 Phase 2-3 trials between 2004 and 2008, mostly in rheumatology and cardiology.

Maxim Belotserkovsky is the Head of Medical Affairs at PSI CRO AG. He is a board-certifi ed physician in internal medicine, rheumatology, anesthesiology and intensive care, and hemodialysis. He is also an Associate Professor of Pathological Physiology. Maxim has more than 20 years of experience in clinical research as an Investigator and Clinical Research Professional, and has authored or co-authored more than 100 publications.

Akhil Kumar
Maxim Kosov
Marcelo Yantorno
Maxim Belotserkovsky
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