Abstract: TH-PO422
Liver Safety of Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD): Interim Data from a European Union Post-Authorization Safety Study (EUPASS)
Session Information
- Genetic Diseases: Cystic - Therapeutic Investigations and Prognosis
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic
Authors
- Kumar, Retesh Kumar, Otsuka Pharmaceutical Europe Ltd, Wexham, United Kingdom
- Lohrmann, Emanuel, Otsuka Pharmaceutical Europe Ltd, Wexham, United Kingdom
- Ezenekwe, Ada, Otsuka Pharmaceutical Development and Commercialization Inc, Princeton, New Jersey, United States
- Nunna, Sasikiran, Otsuka Pharmaceutical Development and Commercialization Inc, Princeton, New Jersey, United States
- Fernandes, Ancilla, Otsuka Pharmaceutical Development and Commercialization Inc, Princeton, New Jersey, United States
- Jaeger, Thomas, Otsuka Pharmaceutical Europe Ltd, Wexham, United Kingdom
- Mccormick, Linda, Otsuka Pharmaceutical Development and Commercialization Inc, Princeton, New Jersey, United States
- George, Vinu, Otsuka Pharmaceutical Development and Commercialization Inc, Princeton, New Jersey, United States
Background
After risk of drug-induced liver injury was detected during tolvaptan clinical development for the treatment of ADPKD, a real-world pharmacovigilance study was required as a condition of EU regulatory approval. We provide an interim-analysis of 6-years of liver safety data from EUPASS.
Methods
This is an interim analysis from a prospective, observational study enrolling patients prescribed tolvaptan for ADPKD in everyday clinical practice. Data are obtained through physician records collected as part of regular standard of care. Per the prescribing label, liver enzymes are monitored monthly for the first 18 months of treatment and once every 3 months thereafter, and patients and providers are required to report adverse events suggestive of liver injury. The data collection period was Oct 2016–Apr 2022. An independent hepatic adjudication committee (HAC) evaluates all DILI cases in EUPASS.
Results
At data cutoff, 2,074 patients had received at least one dose of tolvaptan (median follow-up, 528 days). Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥3 times upper limit of normal (ULN) were found for 65 patients (3.1%). Among these patients, 35 (1.7%) had elevation of ALT/AST > 3 to ≤ 5 times ULN, 21 (1.0 %) had elevation of > 5 to ≤ 10 times ULN, 9 (0.4 %) > 10 times ULN. Tolvaptan was interrupted or withdrawn in 59/65 (90.8%) participants with confirmed ALT/AST ≥3 times ULN, with most transaminase elevations and adverse events resolved or resolving at data cutoff. No laboratory results met criteria for high-risk liver injury (Hy’s Law). As per the assessment of HAC, there was no dose-response relationship.
Conclusion
Regular monitoring facilitates prompt detection of liver adverse events and intervention to reduce risk of severe injury. Data from interim analysis indicate that monitoring and risk minimization measures are effectively mitigating the risk of liver injury. No Hy’s law cases/deaths have been reported.
Funding
- Commercial Support – Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USA