title: Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database.
abstract: BACKGROUND
  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.
authors.affiliation: Hamner-UNC Institute for Drug Safety Sciences, University of North Carolina-Chapel Hill, Research Triangle Park, Chapel Hill, NC, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
authors.affiliation: Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Lewis
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Kaplowitz
authors.affiliation: Washington University School of Medicine, St Louis, MO, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Alpers
authors.affiliation: Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., 2440 Research Blvd, Rockville, MD, 20850, USA.
authors.forename: Jaime D
authors.initials: JD
authors.lastname: Blais
authors.affiliation: Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., 2440 Research Blvd, Rockville, MD, 20850, USA.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Smotzer
authors.affiliation: Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., 2440 Research Blvd, Rockville, MD, 20850, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Krasa
authors.affiliation: Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., 2440 Research Blvd, Rockville, MD, 20850, USA.
authors.forename: John
authors.initials: J
authors.lastname: Ouyang
authors.affiliation: Nephrology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
authors.affiliation: Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., 2440 Research Blvd, Rockville, MD, 20850, USA.
authors.forename: Frank S
authors.initials: FS
authors.lastname: Czerwiec
authors.affiliation: Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., 2440 Research Blvd, Rockville, MD, 20850, USA. Christopher.Zimmer@otsuka-us.com.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Zimmer
mesh_terms: D000328:Adult; D065092:Antidiuretic Hormone Receptor Antagonists / Q000009:adverse effects; D001552:Benzazepines / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis / Q000453:epidemiology*; D016208:Databases, Factual / Q000706:statistics & numerical data*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016891:Polycystic Kidney, Autosomal Dominant / Q000175:diagnosis / Q000453:epidemiology*; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000706:statistics & numerical data*; D012189:Retrospective Studies; D013223:Statistics as Topic / Q000379:methods*; D000077602:Tolvaptan
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D000077602:Tolvaptan