Long-term safety profile of tolvaptan in autosomal dominant polycystic kidney disease patients: TEMPO Extension Japan Trial

Satoru Muto, Tadashi Okada, Moriyoshi Yasuda, Hidetsugu Tsubouchi, Koji Nakajima, Shigeo Horie, Satoru Muto, Tadashi Okada, Moriyoshi Yasuda, Hidetsugu Tsubouchi, Koji Nakajima, Shigeo Horie

Abstract

Aim: The aim of this trial (ClinicalTrials.gov identifier: NCT01280721) was to investigate the long-term safety profile of tolvaptan in Japanese patients with autosomal dominant polycystic kidney disease (ADPKD).

Methods: This open-label multicenter trial was conducted to examine adverse drug reactions (ADRs) related to tolvaptan up to an additional 3 years in 135 Japanese patients who participated in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial at doses of 60-120 mg/d. Blood samples were collected at baseline; at weeks 1, 2, and 3; at month 3; and every 3 months thereafter.

Results: In total, 134/135 (>99%) patients experienced ADRs. The most frequent ADRs were thirst (77.0%), pollakiuria (57.0%), polyuria (37.8%), and hyperuricemia (14.8%). Any unexpected ADRs were not reported in this trial. Most ADRs occurred early during treatment. Fourteen patients (10.4%) experienced hepatic events, and 8 (5.9%) experienced >3-fold increases above the upper limits of normal in serum alanine aminotransferase or aspartate aminotransferase levels between 3 and 9 months following tolvaptan initiation, which recovered after drug interruption. Of the 8 patients, 7 (5.2%) were previously allocated to the placebo arm in the TEMPO 3:4 trial and 4 (3.0%) discontinued due to the hepatic events. One patient (0.7%) was previously allocated to tolvaptan and experienced similar events in the TEMPO 3:4 trial. None of the hepatic ADRs met Hy's Law laboratory criteria.

Conclusion: ADRs observed in this extension trial were similar to those identified in the TEMPO 3:4 trial and hepatic events were not progressive.

Keywords: autosomal dominant polycystic kidney disease; drug-induced liver injury; liver function test; safety profile; tolvaptan.

Conflict of interest statement

Disclosure SH has received honoraria for presentations, paid travels, a payment for writing an expert report, and research funding from Otsuka Pharmaceutical; in addition, he has been a medical advisor of the TEMPO Extension Japan trial. SM has received honoraria for presentations, paid travel, and research funding from Otsuka Pharmaceutical. TO, MY, HT, and KN are employees of Otsuka. SM and SH belong to an endowed department sponsored by Otsuka Pharmaceutical Co, Ltd. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Design of TEMPO Extension Japan Trial. Notes: This trial involved patients who were previously enrolled in the TEMPO 3:4 trial., All participants received tolvaptan. Titration method was according to the previous TEMPO 3:4 trial. Abbreviation: TEMPO, Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes.
Figure 2
Figure 2
Patient flow chart. Abbreviation: TEMPO, Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes.
Figure 3
Figure 3
The number of patients experiencing their first ADRs in the course of the trial. Notes: In the respective patients, the time point of the first ADR observed was noted. Thereafter, the numbers of the patients experiencing first ADR were analyzed every 3 months. Abbreviation: ADR, adverse drug reaction.
Figure 4
Figure 4
Laboratory test results at each time point. Notes: (A) Serum ALT, (B) serum AST, and (C) serum T-Bil levels. Data are expressed as mean ± SD. Ranges for normal values are as follows: ALT, 5–45 U/L; AST, 10–40 U/L; T-Bil, 0.2–1.2 mg/dL. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; T-Bil, total bilirubin; BL, baseline; FU, follow-up; n, number of patients.
Figure 5
Figure 5
Serum sodium and potassium levels at each time point. Notes: Serum (A) sodium and (B) potassium levels. Data are expressed as mean ± SD. Abbreviations: BL, baseline; FU, follow-up; n, number of patients.
Figure 6
Figure 6
Summary of the TEMPO Extension Japan Trial after the TEMPO 3:4 trial., Abbreviation: TEMPO, Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes.

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Source: PubMed

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