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

Watkins PB, Lewis JH, Kaplowitz N, Alpers DH, Blais JD, Smotzer DM, Krasa H, Ouyang J, Torres VE, Czerwiec FS, Zimmer CA - Drug Saf (2015)

Bottom Line: No association with dose or systemic exposure was found.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.

View Article: PubMed Central - PubMed

Affiliation: Hamner-UNC Institute for Drug Safety Sciences, University of North Carolina-Chapel Hill, Research Triangle Park, Chapel Hill, NC, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Time to first elevation of alanine aminotransferase to >3 × upper limit of normal in adjudicated subjects. a TEMPO 3:4: the apparent window of susceptibility is shown as shaded in yellow. All of the tolvaptan cases adjudicated as probable or higher are shown as green arrows and the two Hy’s Law cases are shown as red arrows. b TEMPO 4:4: the Hy’s Law case is shown as a red arrow. TLV tolvaptan
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Fig4: Time to first elevation of alanine aminotransferase to >3 × upper limit of normal in adjudicated subjects. a TEMPO 3:4: the apparent window of susceptibility is shown as shaded in yellow. All of the tolvaptan cases adjudicated as probable or higher are shown as green arrows and the two Hy’s Law cases are shown as red arrows. b TEMPO 4:4: the Hy’s Law case is shown as a red arrow. TLV tolvaptan

Mentions: In TEMPO 3:4, the 16 cases with ALT elevations >3 × ULN that were attributable to tolvaptan (probable or highly likely) were detected between 3 and 18 months after initiation (Fig. 4). For the two Hy’s Law cases, ALT elevations >3 × ULN first occurred between 5 and 9 months post initiation of tolvaptan. All 35 cases adjudicated in the tolvaptan group returned to ≤3 × ULN. The majority of subjects who had discontinued tolvaptan (14/35) returned to ≤3 × ULN within 40 days, whereas the majority of subjects who had continued therapy (21/35) returned to ≤3 × ULN within 120 days (data not shown). There was no correlation between the height of the peak serum ALT and duration of the ALT elevation >3 × ULN (data not shown).Fig. 4


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

Watkins PB, Lewis JH, Kaplowitz N, Alpers DH, Blais JD, Smotzer DM, Krasa H, Ouyang J, Torres VE, Czerwiec FS, Zimmer CA - Drug Saf (2015)

Time to first elevation of alanine aminotransferase to >3 × upper limit of normal in adjudicated subjects. a TEMPO 3:4: the apparent window of susceptibility is shown as shaded in yellow. All of the tolvaptan cases adjudicated as probable or higher are shown as green arrows and the two Hy’s Law cases are shown as red arrows. b TEMPO 4:4: the Hy’s Law case is shown as a red arrow. TLV tolvaptan
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4608984&req=5

Fig4: Time to first elevation of alanine aminotransferase to >3 × upper limit of normal in adjudicated subjects. a TEMPO 3:4: the apparent window of susceptibility is shown as shaded in yellow. All of the tolvaptan cases adjudicated as probable or higher are shown as green arrows and the two Hy’s Law cases are shown as red arrows. b TEMPO 4:4: the Hy’s Law case is shown as a red arrow. TLV tolvaptan
Mentions: In TEMPO 3:4, the 16 cases with ALT elevations >3 × ULN that were attributable to tolvaptan (probable or highly likely) were detected between 3 and 18 months after initiation (Fig. 4). For the two Hy’s Law cases, ALT elevations >3 × ULN first occurred between 5 and 9 months post initiation of tolvaptan. All 35 cases adjudicated in the tolvaptan group returned to ≤3 × ULN. The majority of subjects who had discontinued tolvaptan (14/35) returned to ≤3 × ULN within 40 days, whereas the majority of subjects who had continued therapy (21/35) returned to ≤3 × ULN within 120 days (data not shown). There was no correlation between the height of the peak serum ALT and duration of the ALT elevation >3 × ULN (data not shown).Fig. 4

Bottom Line: No association with dose or systemic exposure was found.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.

View Article: PubMed Central - PubMed

Affiliation: Hamner-UNC Institute for Drug Safety Sciences, University of North Carolina-Chapel Hill, Research Triangle Park, Chapel Hill, NC, USA.

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.

No MeSH data available.


Related in: MedlinePlus