Limits...
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

Evaluation of drug-induced serious hepatotoxicity (e-DISH) plots for a ADPKD (TEMPO 3:4); b non-ADPKD subjects; and (c–e) non-ADPKD subjects by etiology. Peak ALT (x-axis) versus peak total bilirubin (y-axis). Vertical lines correspond to 3 × ULN for ALT. Horizontal lines correspond to 2 × ULN for BT. Subjects in the lower-left quadrant are relatively normal and subjects meeting Hy’s laboratory criteria are shown in the upper-right quadrant. ADKPD autosomal dominant polycystic kidney disease, ALT alanine aminotransferase, BT total bilirubin, PLC placebo, TLV tolvaptan, ULN upper limit of normal
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4608984&req=5

Fig1: Evaluation of drug-induced serious hepatotoxicity (e-DISH) plots for a ADPKD (TEMPO 3:4); b non-ADPKD subjects; and (c–e) non-ADPKD subjects by etiology. Peak ALT (x-axis) versus peak total bilirubin (y-axis). Vertical lines correspond to 3 × ULN for ALT. Horizontal lines correspond to 2 × ULN for BT. Subjects in the lower-left quadrant are relatively normal and subjects meeting Hy’s laboratory criteria are shown in the upper-right quadrant. ADKPD autosomal dominant polycystic kidney disease, ALT alanine aminotransferase, BT total bilirubin, PLC placebo, TLV tolvaptan, ULN upper limit of normal

Mentions: The pivotal TEMPO 3:4 trial included 957 ADPKD subjects who received tolvaptan and 484 who received placebo. An imbalance between tolvaptan- and placebo-treated subjects with ALT >3 × ULN and BT <2 × ULN was also observed in TEMPO 3:4 [40/957 (4.4 %) vs. 5/484 (1.0%), respectively] (Fig. 1a, lower-right quadrant). No imbalance in ALT >3 × ULN between treatment groups was evident at baseline [3/946 (0.32 %) vs. 1/479 (0.21 %), respectively]. Using adjudication criteria, 35 tolvaptan- and 11 placebo-treated subjects were investigated by the independent HAC (Table 2). The likelihood that an event was caused by study medication was assessed as probable or higher in 17 of these subjects, of whom 16 had received tolvaptan and one had received placebo. The presence of possible confounding diagnoses, including risk factors for viral hepatitis, autoimmune hepatitis, fatty liver disease, alcohol consumption, and concomitant use of medications with potential for idiosyncratic transaminase elevations, may have exacerbated the tolvaptan-related hepatotoxicity in some subjects.Fig. 1


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)

Evaluation of drug-induced serious hepatotoxicity (e-DISH) plots for a ADPKD (TEMPO 3:4); b non-ADPKD subjects; and (c–e) non-ADPKD subjects by etiology. Peak ALT (x-axis) versus peak total bilirubin (y-axis). Vertical lines correspond to 3 × ULN for ALT. Horizontal lines correspond to 2 × ULN for BT. Subjects in the lower-left quadrant are relatively normal and subjects meeting Hy’s laboratory criteria are shown in the upper-right quadrant. ADKPD autosomal dominant polycystic kidney disease, ALT alanine aminotransferase, BT total bilirubin, PLC placebo, TLV tolvaptan, ULN upper limit of normal
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4608984&req=5

Fig1: Evaluation of drug-induced serious hepatotoxicity (e-DISH) plots for a ADPKD (TEMPO 3:4); b non-ADPKD subjects; and (c–e) non-ADPKD subjects by etiology. Peak ALT (x-axis) versus peak total bilirubin (y-axis). Vertical lines correspond to 3 × ULN for ALT. Horizontal lines correspond to 2 × ULN for BT. Subjects in the lower-left quadrant are relatively normal and subjects meeting Hy’s laboratory criteria are shown in the upper-right quadrant. ADKPD autosomal dominant polycystic kidney disease, ALT alanine aminotransferase, BT total bilirubin, PLC placebo, TLV tolvaptan, ULN upper limit of normal
Mentions: The pivotal TEMPO 3:4 trial included 957 ADPKD subjects who received tolvaptan and 484 who received placebo. An imbalance between tolvaptan- and placebo-treated subjects with ALT >3 × ULN and BT <2 × ULN was also observed in TEMPO 3:4 [40/957 (4.4 %) vs. 5/484 (1.0%), respectively] (Fig. 1a, lower-right quadrant). No imbalance in ALT >3 × ULN between treatment groups was evident at baseline [3/946 (0.32 %) vs. 1/479 (0.21 %), respectively]. Using adjudication criteria, 35 tolvaptan- and 11 placebo-treated subjects were investigated by the independent HAC (Table 2). The likelihood that an event was caused by study medication was assessed as probable or higher in 17 of these subjects, of whom 16 had received tolvaptan and one had received placebo. The presence of possible confounding diagnoses, including risk factors for viral hepatitis, autoimmune hepatitis, fatty liver disease, alcohol consumption, and concomitant use of medications with potential for idiosyncratic transaminase elevations, may have exacerbated the tolvaptan-related hepatotoxicity in some subjects.Fig. 1

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