Cargando…

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

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 i...

Descripción completa

Detalles Bibliográficos
Autores principales: Watkins, Paul B., Lewis, James H., Kaplowitz, Neil, Alpers, David H., Blais, Jaime D., Smotzer, Dan M., Krasa, Holly, Ouyang, John, Torres, Vicente E., Czerwiec, Frank S., Zimmer, Christopher A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608984/
https://www.ncbi.nlm.nih.gov/pubmed/26188764
http://dx.doi.org/10.1007/s40264-015-0327-3
_version_ 1782395748931862528
author Watkins, Paul B.
Lewis, James H.
Kaplowitz, Neil
Alpers, David H.
Blais, Jaime D.
Smotzer, Dan M.
Krasa, Holly
Ouyang, John
Torres, Vicente E.
Czerwiec, Frank S.
Zimmer, Christopher A.
author_facet Watkins, Paul B.
Lewis, James H.
Kaplowitz, Neil
Alpers, David H.
Blais, Jaime D.
Smotzer, Dan M.
Krasa, Holly
Ouyang, John
Torres, Vicente E.
Czerwiec, Frank S.
Zimmer, Christopher A.
author_sort Watkins, Paul B.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4608984
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Springer International Publishing
record_format MEDLINE/PubMed
spelling pubmed-46089842015-10-21 Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database Watkins, Paul B. Lewis, James H. Kaplowitz, Neil Alpers, David H. Blais, Jaime D. Smotzer, Dan M. Krasa, Holly Ouyang, John Torres, Vicente E. Czerwiec, Frank S. Zimmer, Christopher A. Drug Saf Original Research Article 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. Springer International Publishing 2015-07-19 2015 /pmc/articles/PMC4608984/ /pubmed/26188764 http://dx.doi.org/10.1007/s40264-015-0327-3 Text en © 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.
spellingShingle Original Research Article
Watkins, Paul B.
Lewis, James H.
Kaplowitz, Neil
Alpers, David H.
Blais, Jaime D.
Smotzer, Dan M.
Krasa, Holly
Ouyang, John
Torres, Vicente E.
Czerwiec, Frank S.
Zimmer, Christopher A.
Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database
title Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database
title_full Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database
title_fullStr Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database
title_full_unstemmed Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database
title_short Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database
title_sort clinical pattern of tolvaptan-associated liver injury in subjects with autosomal dominant polycystic kidney disease: analysis of clinical trials database
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608984/
https://www.ncbi.nlm.nih.gov/pubmed/26188764
http://dx.doi.org/10.1007/s40264-015-0327-3
work_keys_str_mv AT watkinspaulb clinicalpatternoftolvaptanassociatedliverinjuryinsubjectswithautosomaldominantpolycystickidneydiseaseanalysisofclinicaltrialsdatabase
AT lewisjamesh clinicalpatternoftolvaptanassociatedliverinjuryinsubjectswithautosomaldominantpolycystickidneydiseaseanalysisofclinicaltrialsdatabase
AT kaplowitzneil clinicalpatternoftolvaptanassociatedliverinjuryinsubjectswithautosomaldominantpolycystickidneydiseaseanalysisofclinicaltrialsdatabase
AT alpersdavidh clinicalpatternoftolvaptanassociatedliverinjuryinsubjectswithautosomaldominantpolycystickidneydiseaseanalysisofclinicaltrialsdatabase
AT blaisjaimed clinicalpatternoftolvaptanassociatedliverinjuryinsubjectswithautosomaldominantpolycystickidneydiseaseanalysisofclinicaltrialsdatabase
AT smotzerdanm clinicalpatternoftolvaptanassociatedliverinjuryinsubjectswithautosomaldominantpolycystickidneydiseaseanalysisofclinicaltrialsdatabase
AT krasaholly clinicalpatternoftolvaptanassociatedliverinjuryinsubjectswithautosomaldominantpolycystickidneydiseaseanalysisofclinicaltrialsdatabase
AT ouyangjohn clinicalpatternoftolvaptanassociatedliverinjuryinsubjectswithautosomaldominantpolycystickidneydiseaseanalysisofclinicaltrialsdatabase
AT torresvicentee clinicalpatternoftolvaptanassociatedliverinjuryinsubjectswithautosomaldominantpolycystickidneydiseaseanalysisofclinicaltrialsdatabase
AT czerwiecfranks clinicalpatternoftolvaptanassociatedliverinjuryinsubjectswithautosomaldominantpolycystickidneydiseaseanalysisofclinicaltrialsdatabase
AT zimmerchristophera clinicalpatternoftolvaptanassociatedliverinjuryinsubjectswithautosomaldominantpolycystickidneydiseaseanalysisofclinicaltrialsdatabase