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

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.

Figures

Fig. 1

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

Fig. 2

Patterns of hepatic transaminase/total bilirubin elevations in the three Hy’s Law cases in TEMPO 3:4 and its open-label extension study TEMPO 4:4. Cases A and B are from TEMPO 3:4, and case C was from TEMPO 4:4 (a prior placebo subject from TEMPO 3:4). Additional information on each case study is presented in Sect. 3. Gray shading in the background represents periods of dosing; white lines correspond to dosing interruptions. ALP alkaline phosphatase, ALT alanine aminotransferase, AST aspartate aminotransferase, BT total bilirubin, ULN upper limit of normal

Fig. 3

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

Fig. 4

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

Fig. 5

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 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