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Variation in Liver Biochemistries in Patients with Decompensated Cirrhosis: Implications for Assessing Drug-Induced Liver Injury in Clinical Trials

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Abstract

Background

Current approaches to detection of drug-induced liver injury (DILI) are generally based on changes from normal in biochemical liver tests. However, limited information is available regarding the proportion of patients with normal versus abnormal biochemical tests, the expected temporal pattern of biochemical abnormalities, or the applicability of current approaches to DILI detection for patients with pre-existing liver disease.

Objective

These analyses aimed to answer the following questions. (1) What proportion of patients have normal versus abnormal biochemical liver tests at study baseline? (2) What is the variability of these biochemical tests on repeat testing? (3) What proportion of patients meet current criteria for discontinuation of treatment? (4) Is an eDISH (evaluation of Drug-Induced Serious Hepatotoxicity) approach likely to be useful in such a study population?

Methods

Biochemical liver test results from 178 patients with clinically decompensated cirrhosis who participated in a 4-month clinical trial of glycerol phenylbutyrate versus placebo for reduction in recurrence rate of hepatic encephalopathy were reviewed to determine fluctuation over time and the applicability of the US FDA DILI guideline and eDISH.

Results

In this cohort, the biochemical tests were frequently abnormal at baseline (aspartate aminotransferase [AST] 42 %, alanine aminotransferase [ALT] 71 %, bilirubin 67 %, international normalized ratio [INR] 62 %) and exhibited substantial variation both pre-dose and following enrollment and dosing. Up to 20 % of patients met current regulatory guidance criteria for consideration of interruption of drug treatment irrespective of treatment group assignment and whether tests were normal or abnormal at baseline, and an eDISH display approach appears unlikely to be informative.

Conclusions

Approaches to DILI detection in patients with pre-existing liver disease will require a more nuanced approach to recognize patterns of potential liver injury.

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References

  1. FDA Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 2009. http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

  2. Berna W, Lee WM, Wendon J, et al. Acute liver failure: a curable disease by 2024? J Hepatol. 2015;62:S112–20.

    Article  Google Scholar 

  3. Watkins PB, Desai M, Berkowitz SD, et al. Evaluation of drug-induced serious hepatotoxicity (eDISH): application of this data organization approach to phase III clinical trials of rivaroxaban after total hip or knee replacement surgery. Drug Saf. 2011;34(3):243–52.

    Article  PubMed  Google Scholar 

  4. Aithal GP, Watkins PB, Andrade RJ, et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 2011;89:807–15.

    Article  Google Scholar 

  5. Giboney PT. Mildly elevated liver transaminase levels in the asymptomatic patient. Am Fam Physician. 2005;71:105–10.

    Google Scholar 

  6. Lazo M, Selvin E, Clark JM. Brief communication: clinical implications of short-term variability in liver function test results. Ann Intern Med. 2008;148:348–52.

    Article  PubMed  Google Scholar 

  7. Rockey DC, Vierling JM, Mantry P, For the HALT-HE Study Group, et al. Randomized, controlled, double blind study of glycerol phenylbutyrate in patients with cirrhosis and episodic hepatic encephalopathy. Hepatology 2014;59:1073–1083.

  8. Fleming TR. Addressing missing data in clinical trials. Ann Intern Med. 2011;154:113–7.

    Article  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Horizon Therapeutics, Inc., 520 Lake Cook Road, Suite 520, Deerfield, IL, 60015, USA

    Marzena Jurek, Masoud Mokhtarani, Dion F. Coakley, Jitendra Ganju, Richard Rowell & Bruce F. Scharschmidt

  2. Baylor College of Medicine, Houston, TX, USA

    John M. Vierling

Authors
  1. Marzena Jurek
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  2. Masoud Mokhtarani
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  3. John M. Vierling
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  4. Dion F. Coakley
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  5. Jitendra Ganju
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  6. Richard Rowell
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  7. Bruce F. Scharschmidt
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Corresponding author

Correspondence to Bruce F. Scharschmidt.

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Financial support

The study was funded by Hyperion Therapeutics, Inc.; subsequently acquired by Horizon Pharma.

Conflict of interest

Dion F. Coakley, Jitendra Ganju, Marzena Jurek, Masoud Mokhtarani, Richard Rowell, Bruce F. Scharschmidt and John M. Vierling are/were employees and stock holders of, or are consultants to, Horizon Pharma (formerly Hyperion Therapeutics).

Ethical approval

The protocol for the original phase II study was designed by Hyperion Therapeutics, Inc. in consultation with the HALT-HE Study Group and the US FDA, and reviewed and approved by the institutional review board (IRB) or ethics committee at each investigative site and/or a central IRB. The protocol conformed to the ethical guideline of the 1975 Declaration of Helsinki. All patients and/or their authorized representatives provided written informed consent.

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Jurek, M., Mokhtarani, M., Vierling, J.M. et al. Variation in Liver Biochemistries in Patients with Decompensated Cirrhosis: Implications for Assessing Drug-Induced Liver Injury in Clinical Trials. Pharm Med 30, 95–101 (2016). https://doi.org/10.1007/s40290-015-0134-2

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  • DOI: https://doi.org/10.1007/s40290-015-0134-2

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