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Kidney Week

Abstract: TH-PO840

Clinical Pattern of Tolvaptan (TLV)-Associated Liver Injury in Autosomal Dominant Polycystic Kidney Disease (ADPKD) Patients: Analysis of Pivotal Clinical Trials

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Alpers, David H., Washington University School of Medicine, St Louis, Missouri, United States
  • Lewis, James H., Georgetown University School of Medicine, Washington, District of Columbia, United States
  • Hunt, Christine M., Duke University Medical Center, Durham, North Carolina, United States
  • Freston, James W., University of Connecticut Health Center, Farmington, South Carolina, United States
  • Torres, Vicente E., Mayo Clinic, Rochester, Minnesota, United States
  • Wang, Wenchyi, Otsuka Pharmaceutical Development & Commercialization, Rockville, Maryland, United States
  • Li, Hui, Otsuka Pharmaceutical Development & Commercialization, Rockville, Maryland, United States
  • Hoke, Molly E., Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey, United States
  • Sergeyeva, Olga, Otsuka Pharmaceuticals, Princeton, New Jersey, United States
  • Estilo, Alvin, Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey, United States

In the TEMPO clinical program, an imbalance in the proportion of pts with elevated aminotransferases >3X upper limit of normal (ULN) was seen vs placebo (PBO). As 3 pts (2 from TEMPO 3:4 [NCT00428948], and 1 from the open-label extension, TEMPO 4:4 (NCT01214421]) met Hy’s Law criteria, increased monitoring frequency was recommended. In the REPRISE clinical program, monitoring was q1m during the first 18m of TLV exposure and q3m thereafter.


An independent, blinded Hepatic Adjudication Committee examined data from REPRISE (NCT02160145) and its open-label extension (NCT02251275) in pts with aminotransferases >3X ULN using the 5-point U.S. DILI Network classification.


In REPRISE 1370 pts were randomized to TLV (AM/PM split doses of 60/30mg or 90/30mg) or PBO. 1362 pts had postbaseline assessments of serum aminotransferases. 72 pts with ALT elevations >3X ULN were reviewed, and 14 were judged to have liver injury at least probably related to the study drug, but without liver failure or persistent liver injury. Elevations began ~2-3 m after study drug initiation and were seen to develop over the course of 12 m. No association with dose or systemic exposure was found, and no pts on TLV (n=681) or PBO (n=685) met the definition of Hy’s Law. In the open-label extension, 1803 pts were enrolled (REPRISE: 60%; TEMPO 4:4: 40%); 1800 received ≥1 TLV dose and were analyzed. 1488 pts (83%) completed the study. The duration of TLV exposure ranged from short (≤1 m) to extended (>42 m), with a median exposure of 651 days. 1267/1800 (70.4%) pts had >18m TLV exposure. 53 cases were adjudicated, and 2 judged as probably related to TLV, but no Hy’s Law cases were identified. The safety profile of TLV in these studies did not differ from that in TEMPO 3:4 except for the absence of Hy’s Law cases, despite more advanced ADPKD pts being included in REPRISE.


In the REPRISE clinical program all cases of probable liver injury were reversible, consistent with earlier experience in TEMPO. No pts met Hy’s Law criteria for more serious liver injury, possibly due to more frequent monitoring and earlier interruption of therapy. (Funding: Otsuka)


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