Modulation of Drug-Induced Liver Injury by Concomitant Medications -Mining Spontaneous Adverse Event Reporting Systems

Presented by Dr. Ayako Suzuki, Duke University

Charlotte

Seminar will be held Friday, April 8 at 1:30 PM in Bioinformatics 105.

ABSTRACT:

Drug-induced liver injury (hereafter DILI) is one of the most common adverse events and has become a critical public health problem over the past decade.1 Concurrently, rates of per-capita prescription medication use have considerably increased during the past years, along with the use of over-the-counter (OTC) medications and dietary supplements.2 Alarmingly, the majority of prescription medication users concurrently used OTC medications and/or dietary supplements and 29% of older adults (57-85 years old) used at least 5 prescription medications simultaneously.2 Concomitant use of multiple medications and dietary supplements will likely modulate drug metabolism, transporter function, and, probably, cellular mechanisms of cytoprotection and repair, which may eventually impact clinical susceptibility and disease course of DILI. Exploring the effect of concomitant medications on DILI events will aid the development of preventive strategies for specific drug treatments and advance our understanding of mechanisms of DILI.

To explore potential impact of comedications on drug-specific DILI, we have been mining large data sets of spontaneous adverse event reporting systems. We’ve identified co-reported drugs (or drug classes) which potentially influence reporting frequency (RF) and clinical outcomes of liver events associated with targeted medication use. Furthermore, based on systematic analysis on the identified drugs (drug classes) plus available bioinformatics (i.e., ‘DILI-pharmaco-ontology’ analysis), we’ve developed a holistic, evidence-based theoretical framework explaining disease mechanisms of human DILI (i.e., ‘theoretical’ epidemiology).

At the seminar, I will present this approach and share the findings from previous data-mining analyses on acetaminophen-associated liver injury using the FDA Adverse Event Reporting System database3 as well as our recent extended data-mining analyses investigating differing DILI (isoniazid, valproic acid, acetaminophen, and amoxicillin/clavulanic acid) in the World Health Organization Safety Report Database, VigiBaseTM. I will also share some data from independent validation analyses using a data set from the NIH-funded Acute Liver Failure Study Group4 and Kaiser electronic medical record system.

References

1. Moore TJ, Cohen MR, Furberg CD. Serious adverse drug events reported to the Food and Drug Administration, 1998-2005. Arch Intern Med 2007;167:1752-9.
2. Qato DM, Alexander GC, Conti RM, Johnson M, Schumm P, Lindau ST. Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States. Jama 2008;300:2867-78.
3. Suzuki A, Yuen N, Walsh J, Papay J, Hunt CM, Diehl AM. Co-medications modulating liver injury and repair influence clinical outcome of acetaminophen-associated liver injury. Clin Gastroenterol Hepatol 2009.
4. Suzuki A, Watkins P, Kaplowitz N, Hunt C, Sanders C, Diehl A, Lee W. Co-Medication with Adrenoreceptor Antagonists Is Associated with Lower MELD Scores At Admission in Patients with Acetaminophen-Induced Acute Liver Failure Gastroenterology 2009;136(5)(Suppl.1):A-810.

Ayako Suzuki, MD, Ph.D.
Department: Medicine, Division: Gastroenterology
Duke University