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

Drug Saf (2015) 38:1103–1113 DOI 10.1007/s40264-015-0327-3 ORIGINAL RESEARCH ARTICLE Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database Paul B. Watkins1 • James H. Lewis2 • Neil Kaplowitz3 • David H. Alpers4 • Jaime D. Blais5 • Dan M. Smotzer5 • Holly Krasa5 • John Ouyang5 • Vicente E. Torres6 • Frank S. Czerwiec5 • Christopher A. Zimmer5 Published online: 19 July 2015 Ó The Author(s) 2015. This article is published with open access at Springerlink.com 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. & Christopher A. Zimmer 1 Hamner-UNC Institute for Drug Safety Sciences, University of North Carolina-Chapel Hill, Research Triangle Park, Chapel Hill, NC, USA 2 Georgetown University School of Medicine, Washington, DC, USA 3 Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 4 Washington University School of Medicine, St Louis, MO, USA 5 Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., 2440 Research Blvd, Rockville, MD 20850, USA 6 Nephrology, Mayo Clinic College of Medicine, Rochester, MN, USA Key Points In patients with autosomal dominant polycystic kidney disease (ADPKD), long-term treatment with tolvaptan can rarely cause severe and potentially lifethreatening liver injury. This injury is typically hepatocellular, occurs between 3 and 18 months after starting tolvaptan, and resolves within 4 months after stopping the drug. A risk of similar liver injury was not detected following exposure to tolvaptan in non-ADPKD patients. 1104 P. B. Watkins et al. 1 Introduction 2 Methods Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by the appearance and slow growth of fluid-filled cysts primarily in the kidneys, but also in the liver and other organs [1, 2]. Over time, the expanding cysts physically displace and obstruct renal tubules, blood vessels and lymphatics, as well as promote apoptosis, atrophy and fibrosis of the renal parenchyma, leading to progressive renal failure [3]. ADPKD was responsible for 2.6 % of patients on dialysis and 9.9 % of patients receiving renal transplants in the USA in 2012 [4]. Studies of animal models implicate the antidiuretic hormone arginine vasopressin and its secondary messenger 30 ,50 -cyclic adenosine monophosphate (cAMP) as promoters of kidney-cyst cell proliferation and luminal fluid secretion [5, 6]. In early animal models the suppression of vasopressin release by vasopressin V2-receptor inhibition slowed disease progression [7, 8]. Because tolvaptan is a V2 receptor antagonist, its use in treating ADPKD was investigated. In the pivotal TEMPO 3:4 (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) trial (ClinicalTrials.gov identifier: NCT00428948 [24]), long-term treatment with tolvaptan was associated with favorable outcomes in subjects with early ADPKD. These favorable outcomes included lower rate of growth in total kidney volume (2.8 vs. 5.5 %; p \ 0.001) and slower decline in kidney function [reciprocal of the serum creatinine level, -2.61 vs. -3.81 (mg per mL)-1 per year; p \ 0.001] [9]. TEMPO 3:4 and its extension trial TEMPO 4:4 (ClinicalTrials.gov identifier: NCT01214421 [25]) were continuously monitored by an Independent Data Monitoring Committee (IDMC) that assessed overall safety, including hepatic function and injury. During the course of continued monitoring of the TEMPO trials, the IDMC recommended increasing the frequency of liver monitoring in the TEMPO 4:4 extension study, from every 6 months to every 3 months. Upon unblinding of the TEMPO 3:4 database, an imbalance in hepatic injury, defined as alanine aminotransferase (ALT) [3 times the upper limit of normal (ULN), was observed for subjects receiving tolvaptan (4.4 %) relative to placebo (1.0 %). To assess the risk of hepatotoxicity, an independent, blinded, expert Hepatic Adjudication Committee (HAC) re-examined subject-level data from all ADPKD clinical trials, as well as data from non-ADPKD subjects who had received long-term tolvaptan therapy in other clinical trials, including patients with hyponatremia [syndrome of inappropriate anti-diuretic hormone release (SIADH)], heart failure, and cirrhosis. The results of this analysis are presented here. 2.1 Subjects The safety databases reviewed here were generated in clinical trials that examined the efficacy and safety of tolvaptan in the treatment of ADPKD. The vast majority of included subjects were from the pivotal, randomized, placebo-controlled TEMPO 3:4 trial (NCT00428948 [24]) [9] and its open-label extension TEMPO 4:4 (NCT01214421 [25]). To be eligible for inclusion in TEMPO 3:4, all subjects had to have an image-confirmed diagnosis of ADPKD, total kidney volume C750 mL and an estimated creatinine clearance rate C60 mL/min. 1445 subjects were enrolled (tolvaptan, 961; placebo, 484) and 1441 had at least one post-baseline assessment of hepatic injury. Tolvaptan was administered twice daily, starting at a morning/afternoon dose of 45/15 mg (...truncated)