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European Biopharmaceutical Review
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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).
Conclusion
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.
References
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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