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Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database.
- Source :
-
Drug safety [Drug Saf] 2015 Nov; Vol. 38 (11), pp. 1103-13. - Publication Year :
- 2015
-
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.<br />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.<br />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.<br />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.
- Subjects :
- Adult
Antidiuretic Hormone Receptor Antagonists adverse effects
Chemical and Drug Induced Liver Injury diagnosis
Female
Humans
Male
Middle Aged
Polycystic Kidney, Autosomal Dominant diagnosis
Randomized Controlled Trials as Topic methods
Retrospective Studies
Tolvaptan
Benzazepines adverse effects
Chemical and Drug Induced Liver Injury epidemiology
Databases, Factual statistics & numerical data
Polycystic Kidney, Autosomal Dominant epidemiology
Randomized Controlled Trials as Topic statistics & numerical data
Statistics as Topic methods
Subjects
Details
- Language :
- English
- ISSN :
- 1179-1942
- Volume :
- 38
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Drug safety
- Publication Type :
- Academic Journal
- Accession number :
- 26188764
- Full Text :
- https://doi.org/10.1007/s40264-015-0327-3