Abstract | INTRODUCTION: 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 | Paul B Watkins, James H Lewis, Neil Kaplowitz, David H Alpers, Jaime D Blais, Dan M Smotzer, Holly Krasa, John Ouyang, Vicente E Torres, Frank S Czerwiec, Christopher A Zimmer |
Journal | Drug safety
(Drug Saf)
Vol. 38
Issue 11
Pg. 1103-13
(Nov 2015)
ISSN: 1179-1942 [Electronic] New Zealand |
PMID | 26188764
(Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Antidiuretic Hormone Receptor Antagonists
- Benzazepines
- Tolvaptan
|
Topics |
- Adult
- Antidiuretic Hormone Receptor Antagonists
(adverse effects)
- Benzazepines
(adverse effects)
- Chemical and Drug Induced Liver Injury
(diagnosis, epidemiology)
- Databases, Factual
(statistics & numerical data)
- Female
- Humans
- Male
- Middle Aged
- Polycystic Kidney, Autosomal Dominant
(diagnosis, epidemiology)
- Randomized Controlled Trials as Topic
(methods, statistics & numerical data)
- Retrospective Studies
- Statistics as Topic
(methods)
- Tolvaptan
|