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

Patterns of hepatic transaminases/total bilirubin elevations in cases representative of the signature profile. Case A represents a subject whose ALT continued to rise transiently post-tolvaptan discontinuation prior to a return to <1 × ULN (a). Cases B and C experienced similar ALT elevations to case A; however, both observed an immediate elevation in ALT upon re-challenge with tolvaptan (b and c). Both subjects subsequently returned to <1 × ULN upon discontinuation. Cases D and E are representative examples of subjects whose ALT normalized while on tolvaptan (d and e). Gray shading in the background represents periods of dosing, darker shades of gray represent higher doses of tolvaptan; white lines correspond to dosing interruptions. ALP alkaline phosphatase, ALT alanine aminotransferase, AST aspartate aminotransferase, BILI bilirubin, ULN upper limit of normal
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4608984&req=5

Fig5: Patterns of hepatic transaminases/total bilirubin elevations in cases representative of the signature profile. Case A represents a subject whose ALT continued to rise transiently post-tolvaptan discontinuation prior to a return to <1 × ULN (a). Cases B and C experienced similar ALT elevations to case A; however, both observed an immediate elevation in ALT upon re-challenge with tolvaptan (b and c). Both subjects subsequently returned to <1 × ULN upon discontinuation. Cases D and E are representative examples of subjects whose ALT normalized while on tolvaptan (d and e). Gray shading in the background represents periods of dosing, darker shades of gray represent higher doses of tolvaptan; white lines correspond to dosing interruptions. ALP alkaline phosphatase, ALT alanine aminotransferase, AST aspartate aminotransferase, BILI bilirubin, ULN upper limit of normal

Mentions: The timing of the onset of the liver injury was not always known; the first blood sample obtained by the central laboratory was at the end of the 3-week titration period. Per protocol, the next assessment of liver chemistries was not until the 4-month visit (Fig. 4), but local laboratory values were sometimes available prior to this date. Examples of liver enzyme patterns from representative cases are shown in Fig. 5. Nearly half of the patients (10/21) were able to continue therapy with ALT levels that remained <3 × ULN after recovery, whereas the remaining patients (11/21) exhibited rapid transaminase elevations following re-challenge with therapy that led to discontinuation, but subsequently returned to normal over 1–4 months. No patient who was re-challenged in this manner met criteria for acute liver failure.Fig. 5


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)

Patterns of hepatic transaminases/total bilirubin elevations in cases representative of the signature profile. Case A represents a subject whose ALT continued to rise transiently post-tolvaptan discontinuation prior to a return to <1 × ULN (a). Cases B and C experienced similar ALT elevations to case A; however, both observed an immediate elevation in ALT upon re-challenge with tolvaptan (b and c). Both subjects subsequently returned to <1 × ULN upon discontinuation. Cases D and E are representative examples of subjects whose ALT normalized while on tolvaptan (d and e). Gray shading in the background represents periods of dosing, darker shades of gray represent higher doses of tolvaptan; white lines correspond to dosing interruptions. ALP alkaline phosphatase, ALT alanine aminotransferase, AST aspartate aminotransferase, BILI bilirubin, ULN upper limit of normal
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig5: Patterns of hepatic transaminases/total bilirubin elevations in cases representative of the signature profile. Case A represents a subject whose ALT continued to rise transiently post-tolvaptan discontinuation prior to a return to <1 × ULN (a). Cases B and C experienced similar ALT elevations to case A; however, both observed an immediate elevation in ALT upon re-challenge with tolvaptan (b and c). Both subjects subsequently returned to <1 × ULN upon discontinuation. Cases D and E are representative examples of subjects whose ALT normalized while on tolvaptan (d and e). Gray shading in the background represents periods of dosing, darker shades of gray represent higher doses of tolvaptan; white lines correspond to dosing interruptions. ALP alkaline phosphatase, ALT alanine aminotransferase, AST aspartate aminotransferase, BILI bilirubin, ULN upper limit of normal
Mentions: The timing of the onset of the liver injury was not always known; the first blood sample obtained by the central laboratory was at the end of the 3-week titration period. Per protocol, the next assessment of liver chemistries was not until the 4-month visit (Fig. 4), but local laboratory values were sometimes available prior to this date. Examples of liver enzyme patterns from representative cases are shown in Fig. 5. Nearly half of the patients (10/21) were able to continue therapy with ALT levels that remained <3 × ULN after recovery, whereas the remaining patients (11/21) exhibited rapid transaminase elevations following re-challenge with therapy that led to discontinuation, but subsequently returned to normal over 1–4 months. No patient who was re-challenged in this manner met criteria for acute liver failure.Fig. 5

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