Drug Induced Liver Injury in Premarketing Clinical Trials
DILI (Drug Induced Liver Injury) is a rare but potentially fatal adverse drug reaction.
The evaluation of DILI is critical because most drugs that cause severe DILI do so infrequently and usual drug development databases with up to a few thousand subjects exposed to a new drug will not reveal any cases.
Such databases, on the other hand, may show evidence or signals of a drug ‘ s potential for severe DILI if clinical and laboratory data are properly assessed for evidence of lesser injury that may not be severe but could predict the ability to cause more severe injuries.
For the past 50 years, DILI has been a very common cause of safety-related drug marketing withdrawals.
Here are some examples of such drug withdrawals:
- Tolcapone, troglitazone, trovafloxacin, bromfenac, nefazodone, lumiracoxib and sitaxentan.
- Drugs that were not approved in the United States because their hepatotoxicity was identified during European marketing – ibufenac, perhexiline, alpidem.
- Drugs that were not approved in the United States because premarketing data revealed the possibility of severe DILI: dilevalol, tasosartan, ximelagatran.
Mechanism and Types of DILI
Despite their rarity, both idiosyncratic and indirect DILI can lead to severe and sometimes fatal liver injury.
DILI reactions are usually categorized as follows:
DILI Categories
Signals of DILI and Hy’s Law
Hy’s Law is essentially a translation of Zimmerman’s finding that hyperbilirubinemia
caused by pure hepatocellular injury is an ominous sign of a drug’s potential to
cause substantial liver injury.
In a summary, Hy‘s Law cases consist of the following three elements:
1
2
3
According to Hy‘s law, there is a 10–
50% risk that a patient will develop acute liver failure (ALF), which can lead to death or liver transplantation.
The presence of even one or two such cases in a clinical trial programme is significant because it indicates a higher risk for idiosyncratic ALF in a postmarket population treated with the same medication under equivalent conditions
Severity of DILI
References
- Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 2005;4:489-99.
- Kullak-Ublick GA,Andrade RJ, Merz M, End P, Benesic A, Gerbes AL, et al. Drug induced liver injury: recent advances in diagnosis and risk assessment. Gut 2017;66:1154-1164.
- Davern TJ, Chalasani N. Drug induced liver injury in clinical trials: as rare as hens’ teeth. Am J Gastroenterol. 2009;104:1159-61.
- Aithal GP, Watkins PB, Andrade RJ, et al. Case definition and phenotype standardization in drug induced liver injury. Clin Pharmacol Ther 2011;89:806-15.
- Watkins PB, Seligman PJ, Pears JS, Avigan MI, Senior JR. Using controlled clinical trials to learn more about acute drug induced liver injury. Hepatology 2008; 48(5):1680-1689.
- Drug induced liver injury (DILI): Current status and future directions for drug development and the post-market setting. A consensus by a CIOMS Working Group. Geneva, Switzerland: Council for International Organizations of Medical Sciences (CIOMS), 2020.
- Guidance for Industry Drug Induced Liver Injury: Premarketing Clinical Evaluation. U S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation and Research (CBER). July 2009. Drug Safety.
Authors
Dr. Sumit Verma MD, DNB - President, Clinical Safety and PV
Dr. Yogesh Gulati MD - Sr. Safety Physician, Clinical Safety and PV
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