Liver safety of tolvaptan in patients with autosomal dominant polycystic kidney disease: interim data from a post-authorization safety study.

Background: After the risk of drug-induced liver injury was detected during tolvaptan clinical development for the treatment of autosomal dominant polycystic kidney disease (ADPKD), a post-marketing pharmacovigilance study was required for European Union regulatory approval. Methods: This is an interim analysis from a prospective, observational study enrolling patients prescribed tolvaptan for ADPKD in routine clinical practice. Data were obtained through physician records collected during regular care. Per the prescribing label, liver transaminases were to be monitored monthly for the first 18 months of treatment and once every 3 months thereafter. Patients and physicians were required to report adverse events suggestive of serious and potentially fatal liver injury. Data collection was from October 2016 to April 2022. Results: Of 2074 patients (median follow-up 528 days), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥3 times the upper limit of normal (ULN) were reported in 75 (3.6%) patients. At data cut-off, the enzyme elevations were confirmed for 65 patients. Among the 65 confirmed patients, in addition to transaminase elevations, there were 69 adverse events suggestive of liver injury. Tolvaptan was interrupted or withdrawn in 59/65 (90.8%) participants with confirmed ALT or AST ≥3 times the ULN, with most transaminase elevations and adverse events resolved or resolving at data cut-off. No liver enzyme elevations met laboratory criteria for Hy's law cases. Conclusions: Transaminase elevations occurred post-marketing in a similar proportion of patients as reported in clinical trials (4.4-5.6%). Regular monitoring per label facilitates prompt detection of liver adverse events and intervention to mitigate the risk of severe injury.