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      Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database

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          Abstract

          Introduction

          Subjects with autosomal dominant polycystic kidney disease (ADPKD) who were taking tolvaptan experienced aminotransferase elevations more frequently than those on placebo in the TEMPO 3:4 (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) clinical trial.

          Methods

          An independent, blinded, expert Hepatic Adjudication Committee re-examined data from TEMPO 3:4 and its open-label extension TEMPO 4:4, as well as from long-term (>14 months) non-ADPKD tolvaptan trials, using the 5-point Drug-Induced Liver Injury Network classification.

          Results

          In TEMPO 3:4, 1445 subjects were randomized 2:1 (tolvaptan vs. placebo) and 1441 had post-baseline assessments of hepatic injury. Sixteen patients on tolvaptan and one on placebo had significant aminotransferase elevations judged to be at least probably related to study drug. No association with dose or systemic exposure was found. Two of 957 subjects taking tolvaptan (0.2 %) and zero of 484 taking placebo met the definition of a Hy’s Law case. One additional Hy’s Law case was identified in a TEMPO 4:4 subject who had received placebo in the lead study. The onset of a hepatocellular injury occurred between 3 and 18 months after starting tolvaptan, with gradual resolution over the subsequent 1–4 months. None of the events were associated with liver failure or chronic liver injury/dysfunction. No imbalance in hepatic events was observed between tolvaptan and placebo in lower-dose clinical trials of patients with hyponatremia, heart failure, or cirrhosis.

          Conclusions

          Although hepatocellular injury following long-term tolvaptan treatment in ADPKD subjects was infrequent and reversible, the potential for serious irreversible injury exists. Regular monitoring of transaminase levels is warranted in this patient population.

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          Most cited references17

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          Autosomal dominant polycystic kidney disease.

          Autosomal dominant polycystic kidney disease is the most prevalent, potentially lethal, monogenic disorder. It is associated with large interfamilial and intrafamilial variability, which can be explained to a large extent by its genetic heterogeneity and modifier genes. An increased understanding of the disorder's underlying genetic, molecular, and cellular mechanisms and a better appreciation of its progression and systemic manifestations have laid out the foundation for the development of clinical trials and potentially effective treatments.
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            Clinical practice. Autosomal dominant polycystic kidney disease.

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              The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains.

              Characterization of the polycystic kidney disease 1 (PKD1) gene has been complicated by genomic rearrangements on chromosome 16. We have used an exon linking strategy, taking RNA from a cell line containing PKD1 but not the duplicate loci, to clone a cDNA contig of the entire transcript. The transcript consists of 14,148 bp (including a correction to the previously described C terminus), distributed among 46 exons spanning 52 kb. The predicted PKD1 protein, polycystin, is a glycoprotein with multiple transmembrane domains and a cytoplasmic C-tail. The N-terminal extracellular region of over 2,500 aa contains leucine-rich repeats, a C-type lectin, 16 immunoglobulin-like repeats and four type III fibronectin-related domains. Our results indicate that polycystin is an integral membrane protein involved in cell-cell/matrix interactions.
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                Author and article information

                Contributors
                240-683-3159 , Christopher.Zimmer@otsuka-us.com
                Journal
                Drug Saf
                Drug Saf
                Drug Safety
                Springer International Publishing (Cham )
                0114-5916
                1179-1942
                19 July 2015
                19 July 2015
                2015
                : 38
                : 11
                : 1103-1113
                Affiliations
                [ ]Hamner-UNC Institute for Drug Safety Sciences, University of North Carolina-Chapel Hill, Research Triangle Park, Chapel Hill, NC USA
                [ ]Georgetown University School of Medicine, Washington, DC USA
                [ ]Keck School of Medicine, University of Southern California, Los Angeles, CA USA
                [ ]Washington University School of Medicine, St Louis, MO USA
                [ ]Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., 2440 Research Blvd, Rockville, MD 20850 USA
                [ ]Nephrology, Mayo Clinic College of Medicine, Rochester, MN USA
                Article
                327
                10.1007/s40264-015-0327-3
                4608984
                26188764
                d431399b-d5d6-455f-bdd7-a650bb50b86f
                © The Author(s) 2015

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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                © Springer International Publishing Switzerland 2015

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