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

Estimated tolvaptan exposure in TEMPO 3:4 for subjects adjudicated as probable or higher. Exposures at each of the three doses for all subjects with measurable tolvaptan concentrations are represented by box and whisker plots which summarize daily steady-state exposure, AUC, predicted using individual empirical Bayesian estimates from the population pharmacokinetic model at the individual modal dose. Tolvaptan exposures at the dose taken at the time of the onset of the first hepatic event, for each of the subjects adjudicated as probable or higher is represented as an “×”. Hy’s Law cases are shown as arrows. Whiskers represent the 10th and 90th percentiles, black dots represent the 5th and 95th percentiles. AUC area under the plasma concentration–time curve
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4608984&req=5

Fig3: Estimated tolvaptan exposure in TEMPO 3:4 for subjects adjudicated as probable or higher. Exposures at each of the three doses for all subjects with measurable tolvaptan concentrations are represented by box and whisker plots which summarize daily steady-state exposure, AUC, predicted using individual empirical Bayesian estimates from the population pharmacokinetic model at the individual modal dose. Tolvaptan exposures at the dose taken at the time of the onset of the first hepatic event, for each of the subjects adjudicated as probable or higher is represented as an “×”. Hy’s Law cases are shown as arrows. Whiskers represent the 10th and 90th percentiles, black dots represent the 5th and 95th percentiles. AUC area under the plasma concentration–time curve

Mentions: The two Hy’s Law cases had received the highest dose of tolvaptan administered in the study (120 mg/day split into morning/evening doses of 90/30 mg). In both cases ALT and BT returned to <3 × ULN and <2 × ULN, respectively, following withdrawal from tolvaptan (Fig. 2). Although both Hy’s Law cases occurred at the highest administered dose, subjects adjudicated as probable or higher were generally distributed across all doses and exposures, with no significant difference in the area under the concentration–time curve (p = 0.7543), suggesting no clear dose dependence (Fig. 3). This finding is supported by a Fisher exact test that failed to identify a statistical relationship between dose and hepatotoxicity (p = 0.3464). While no association with dose of exposure was found, additional research has been initiated to further investigate the role of dose and exposure on the risk of hepatic injury.Fig. 2


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)

Estimated tolvaptan exposure in TEMPO 3:4 for subjects adjudicated as probable or higher. Exposures at each of the three doses for all subjects with measurable tolvaptan concentrations are represented by box and whisker plots which summarize daily steady-state exposure, AUC, predicted using individual empirical Bayesian estimates from the population pharmacokinetic model at the individual modal dose. Tolvaptan exposures at the dose taken at the time of the onset of the first hepatic event, for each of the subjects adjudicated as probable or higher is represented as an “×”. Hy’s Law cases are shown as arrows. Whiskers represent the 10th and 90th percentiles, black dots represent the 5th and 95th percentiles. AUC area under the plasma concentration–time curve
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Estimated tolvaptan exposure in TEMPO 3:4 for subjects adjudicated as probable or higher. Exposures at each of the three doses for all subjects with measurable tolvaptan concentrations are represented by box and whisker plots which summarize daily steady-state exposure, AUC, predicted using individual empirical Bayesian estimates from the population pharmacokinetic model at the individual modal dose. Tolvaptan exposures at the dose taken at the time of the onset of the first hepatic event, for each of the subjects adjudicated as probable or higher is represented as an “×”. Hy’s Law cases are shown as arrows. Whiskers represent the 10th and 90th percentiles, black dots represent the 5th and 95th percentiles. AUC area under the plasma concentration–time curve
Mentions: The two Hy’s Law cases had received the highest dose of tolvaptan administered in the study (120 mg/day split into morning/evening doses of 90/30 mg). In both cases ALT and BT returned to <3 × ULN and <2 × ULN, respectively, following withdrawal from tolvaptan (Fig. 2). Although both Hy’s Law cases occurred at the highest administered dose, subjects adjudicated as probable or higher were generally distributed across all doses and exposures, with no significant difference in the area under the concentration–time curve (p = 0.7543), suggesting no clear dose dependence (Fig. 3). This finding is supported by a Fisher exact test that failed to identify a statistical relationship between dose and hepatotoxicity (p = 0.3464). While no association with dose of exposure was found, additional research has been initiated to further investigate the role of dose and exposure on the risk of hepatic injury.Fig. 2

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