Clinical Pattern of Tolvaptan-Associated Liver Injury in Trial Participants With Autosomal Dominant Polycystic Kidney Disease (ADPKD): An Analysis of Pivotal Clinical Trials.

RATIONALE & OBJECTIVE: Tolvaptan is associated with risk of drug-induced liver injury when used to treat autosomal dominant polycystic kidney disease (ADPKD). After this risk was described based on the clinical trials TEMPO 3:4 and TEMPO 4:4, additional data from the REPRISE trial and a long-term extension of TEMPO 4:4, REPRISE, and other tolvaptan trials in ADPKD have become available. To further characterize the hepatic safety profile of tolvaptan, an analysis of the expanded dataset was conducted. STUDY DESIGN: Analysis of safety data from prospective clinical trials of tolvaptan. SETTING & PARTICIPANTS: Multicenter clinical trials including more than 2,900 tolvaptan-treated participants, more than 2,300 with at least 18 months of drug exposure. INTERVENTION: Tolvaptan administered twice daily in split-dose regimens. OUTCOMES: Frequency of liver enzyme level increases detected by regular laboratory monitoring. RESULTS: In the placebo-controlled REPRISE trial, more tolvaptan- than placebo-treated participants (38 of 681 [5.6%] vs 8 of 685 [1.2%]) experienced alanine aminotransferase level increases to >3× the upper limit of normal (ULN), similar to TEMPO 3:4 (40 of 957 [4.4%] vs 5 of 484 [1.0%]). No participant in REPRISE or the long-term extension experienced concurrent alanine aminotransferase level increases to >3× ULN and total bilirubin increases to >2× ULN ("Hy's Law" laboratory criteria). Based on the expanded dataset, liver enzyme increases most often occurred within 18 months after tolvaptan initiation and were less frequent thereafter. Increased levels returned to normal or near normal after treatment interruption or discontinuation. Thirty-eight patients were rechallenged with tolvaptan after the initial drug-induced liver injury episode, with return of liver enzyme level increases in 30; 1 additional participant showed a clinical "adaptation" after the initial episode, with resolution of the enzyme level increases despite continuation of tolvaptan. LIMITATIONS: Retrospective analysis. CONCLUSIONS: The absence of Hy's Law cases in REPRISE and the long-term extension trial support monthly liver enzyme monitoring during the first 18 months of tolvaptan exposure and every 3 months thereafter to detect and manage enzyme level increases, as is recommended on the drug label. FUNDING: Otsuka Pharmaceutical Development & Commercialization, Inc. TRIAL REGISTRATION: Trials included in the dataset were registered at ClinicalTrials.gov with study numbers NCT00428948 (TEMPO 3:4), NCT01214421 (TEMPO 4:4), NCT02160145 (REPRISE), and NCT02251275 (long-term extension).

Industry Review of Best Practices for Risk Management of Drug-Induced Liver Injury from Development to Real-World Use.

The relative treatment benefit of a drug for patients during development, marketing authorization review, or after approval includes an assessment of the risk of drug-induced liver injury (DILI). In this article, the Pharmacovigilance and Risk Mitigation Working Group of the IQ-DILI Initiative launched in June 2016 within the International Consortium for Innovation and Quality in Pharmaceutical Development presents and reviews three key topics for essential risk management activities to identify, characterize, monitor, mitigate, and communicate DILI risk associated with small molecules during drug development. The three topics are: (1) Current best practices for characterizing the DILI phenotype and the severity and incidence of DILI in the treatment population, including DILI identification, prediction and recovery. (2) Characterization of the relative treatment benefit for patients who will be exposed to a drug and the attendant risk of DILI in conjunction with existing global risk mitigation strategies. (3) Implementation of risk mitigation strategies during drug development highlighting patient factors, healthcare settings and site of product administration, and prescriber and healthcare provider factors. Industry guidance is provided for assessing whether the product labeling is sufficient to minimize the risk of DILI or whether a United States Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) or European Medicines Agency (EMA) Risk Management Plan (RMP) with additional Risk Minimization Measures (aRMM) is needed.

The relative treatment benefit of a drug for patients during development, marketing authorization review or after approval includes an assessment of the risk of drug-induced liver injury (DILI). Reported incidences of DILI range from 0.74 to 19 per 100,000, and laboratory criteria and/or clinical outcome determine the severity of DILI. At least 10% of patients who develop jaundice caused by DILI (Hy's Law cases) develop liver failure (i.e., severe DILI). A drug's liver safety profile can be assessed using Evaluation of Drug-Induced Serious Hepatotoxicity Plots. Specific recommendations for monitoring DILI in the post-marketing setting depend on characterization of the phenotype during drug development. Risk mitigation tools include additional educational mechanisms, and risk minimization measures include Elements To Assure Safe Use (ETASU) for healthcare professionals, administration sites, and patients. The overall aim of risk management is to ensure that the benefit of a particular product exceeds the risks as far as possible for the individual patient and for the target population.

Evaluating the impact of a Risk Evaluation and Mitigation Strategy with tolvaptan to monitor liver safety in patients with autosomal dominant polycystic kidney disease.

Background: On approval of JYNARQUE (tolvaptan) for use in patients with autosomal dominant polycystic kidney disease (ADPKD) at risk for rapid progression, the US Food and Drug Administration required a Risk Evaluation and Mitigation Strategy (REMS) from the sponsor, which includes collection of post marketing liver safety data. Methods: This is a retrospective interim analysis of the ongoing REMS. The period evaluated was from REMS implementation (14 May 2018) at tolvaptan commercialization to the analysis cutoff date (23 February 2021). Patients were previously tolvaptan-naïve and initiated tolvaptan in the post marketing setting. Reports of possible severe drug-induced liver injury (DILI) were evaluated for severity based on the evidence obtained (e.g. liver enzyme levels, symptoms, diagnostic tests and event outcomes). The incidence of DILI was compared between the REMS and tolvaptan clinical trials in ADPKD. Results: Among 6711 REMS patients, 60 (0.9%) cases of possible severe DILI were reported, 4 of which were confirmed as serious and potentially fatal by the sponsor. One of these four patients met Hy's law criteria. In all four patients, liver enzymes normalized after tolvaptan discontinuation. The duration of tolvaptan exposure in the REMS is currently shorter than in completed clinical trials, but within this limitation, the incidence of possible severe DILI was lower in the REMS than in clinical trials (incidence rate ratio 0.587; P = .000411). Conclusions: In interim data on >6000 tolvaptan REMS patients, <1% experienced possible severe DILI. Monthly monitoring, as described in the tolvaptan prescribing information, enables the prompt detection of liver enzyme abnormalities and appropriate drug discontinuation.

Using Tolvaptan to Treat Hyponatremia: Results from a Post-authorization Pharmacovigilance Study.

INTRODUCTION: Hyponatremia is a common condition of varying etiology among hospitalized patients and is associated with adverse outcomes. Treatment to normalize serum sodium is advisable. Tolvaptan received European Union marketing authorization for hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Post-marketing pharmacovigilance activities were required to characterize the safety profile of tolvaptan more fully in this population, which is often elderly with a high burden of comorbid illness. METHODS: This was a prospective, observational, multinational, post-authorization pharmacovigilance study (NCT01228682) in seven European countries. Hospitalized patients were enrolled who received tolvaptan for hyponatremia associated with SIADH and consented to data collection. Tolvaptan was initiated and assessments performed at physician discretion per local standards of care. To reflect actual clinical practice, no assessments or procedures were required outside the standard of care. Patients who continued to receive long-term tolvaptan following hospital discharge and provided consent received follow-up from their community physicians. RESULTS: A total of 252 patients (mean age 70.6 years) enrolled. Mean tolvaptan treatment duration was 139.4 days, median 18.5 (range 1-1130) days; most frequent dose was 15 mg/day (used in 75% of patients). Serum sodium increased from baseline (mean 123.2 mmol/l) during treatment week 1 and remained stable during follow-up, with little difference across doses of 7.5, 15, and 30 mg/day. Hyponatremia symptoms (e.g., confusion, unsteady gait, lethargy) were present in 122/252 (48.4%) patients at pre-treatment baseline, decreasing to 46/252 (18.3%) during treatment. Sixty-two patients (24.6%; mean baseline serum sodium 120 mmol/l) experienced rapid correction of hyponatremia within 72 h. No osmotic demyelination syndrome occurred. CONCLUSION: In clinical practice, tolvaptan improved serum sodium and decreased hyponatremia symptoms in hyponatremia secondary to SIADH. Serum sodium should be monitored during treatment to minimize risk of rapid correction. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01228682.

Hospitalized patients often experience abnormally low blood sodium levels (hyponatremia), which can cause significant symptoms and poses a serious health risk (Wald et al. in Arch Intern Med 170:294­302, 2010). Yet, increasing sodium levels too rapidly in these patients can unintentionally cause osmotic demyelination syndrome, resulting in long-term neurologic damage or death. Tolvaptan was approved in the European Union to treat one type of hyponatremia caused by a hormonal imbalance known as the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Tolvaptan effectively increased patient sodium levels in clinical trials, but real-world data are needed to understand tolvaptan treatment more fully in everyday clinical practice. We evaluated patterns of use, efficacy, and safety of tolvaptan in patients treated in hospitals and after discharge for hyponatremia due to SIADH. Tolvaptan was correctly used to treat only hyponatremia caused by SIADH in nearly all of the 252 patients studied. Patient sodium levels increased in the first week of tolvaptan treatment and then stabilized. Hyponatremia symptoms, such as confusion, nausea, tiredness, and dizziness, were present in 48.4% of patients before treatment and in 18.3% after starting tolvaptan. Consistent with earlier studies, some patients (24.6%) experienced excessively rapid correction of hyponatremia. However, no subsequent neurologic problems or deaths were attributed to the rapid correction, which suggests that medical providers were carefully monitoring and managing sodium levels to prevent serious consequences. Our study indicates that tolvaptan is being used safely and effectively to treat hyponatremia due to SIADH in a patient population with complex medical needs.

Using an Automated Algorithm to Identify Potential Drug-Induced Liver Injury Cases in a Pharmacovigilance Database.

INTRODUCTION: Drug-induced liver injury (DILI) is the most frequent cause of acute liver failure in North America and Europe, but it is often missed because of unstandardized diagnostic methods and criteria. This study aimed to develop and validate an automated algorithm to identify potential DILI cases in routine pharmacovigilance (PV) activities. METHODS: Post-marketing hepatic adverse events reported for a potentially hepatotoxic drug in a global PV database from 19 March 2017 to 18 June 2018 were assessed manually and with the automated algorithm. The algorithm provided case assessments by applying pre-specified criteria to all case data and narratives simultaneously. RESULTS: A total of 1456 cases were included for analysis and assessed manually. Sufficient data for algorithm assessment were available for 476 cases (32.7%). Of these cases, manual assessment identified 312 (65.5%) potential DILI cases while algorithm assessment identified 305 (64.1%) potential DILI cases. Comparison of manual and algorithm assessments demonstrated a sensitivity of 97.8% and a specificity of 79.3% for the algorithm. Given the prevalence of potential DILI cases in the population studied, the algorithm was calculated to have positive predictive value 56.3% and negative predictive value 99.2%. The time required for manual review compared to algorithm review suggested that application of the algorithm prior to manual screening would have resulted in a time savings of 42.2%. CONCLUSION: An automated algorithm to identify potential DILI cases was developed and successfully implemented. The algorithm demonstrated a high sensitivity, a high negative predictive value, along with significant efficiency and utility in a real-time PV database.

Overview of Causality Assessment for Drug-Induced Liver Injury (DILI) in Clinical Trials.

Causality assessment for suspected drug-induced liver injury (DILI) during drug development and following approval is challenging. The IQ DILI Causality Working Group (CWG), in collaboration with academic and regulatory subject matter experts (SMEs), developed this manuscript with the following objectives: (1) understand and describe current practices; (2) evaluate the utility of new tools/methods/practice guidelines; (3) propose a minimal data set needed to assess causality; (4) define best practices; and (5) promote a more structured and universal approach to DILI causality assessment for clinical development. To better understand current practices, the CWG performed a literature review, took a survey of member companies, and collaborated with SMEs. Areas of focus included best practices for causality assessment during clinical development, utility of adjudication committees, and proposals for potential new avenues to improve causality assessment. The survey and literature review provided renewed understanding of the complexity and challenges of DILI causality assessment as well as the use of non-standardized approaches. Potential areas identified for consistency and standardization included role and membership of adjudication committees, standardized minimum dataset, updated assessment tools, and best practices for liver biopsy and rechallenge in the setting of DILI. Adjudication committees comprised of SMEs (i.e., utilizing expert opinion) remain the standard for DILI causality assessment. A variety of working groups continue to make progress in pursuing new tools to assist with DILI causality assessment. The minimum dataset deemed adequate for causality assessment provides a path forward for standardization of data collection in the setting of DILI. Continued progress is necessary to optimize and advance innovative tools necessary for the scientific, pharmaceutical, and regulatory community.

A Post Hoc Analysis of Statin Use in Tolvaptan Autosomal Dominant Polycystic Kidney Disease Pivotal Trials.

BACKGROUND AND OBJECTIVES: Tolvaptan is approved to slow kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. Because in vitro studies indicated that the tolvaptan oxobutyric acid metabolite inhibits organic anion-transporting polypeptide (OATP)1B1 and OATP1B3, United States prescribing information advises avoiding concurrent use with OATP1B1/1B3 substrates, including hepatic hydroxymethyl glutaryl-CoA reductase inhibitors (statins). This post hoc analysis of the pivotal phase 3 tolvaptan trials (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes [TEMPO] 3:4 trial [NCT00428948] and Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD [REPRISE] trial [NCT02160145]) examined the safety of concurrent tolvaptan/statin use. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The trials randomized a combined total of 2815 subjects with early- to late-stage ADPKD to tolvaptan (n=1644) or placebo (n=1171) for 3 years (TEMPO 3:4) and 1 year (REPRISE). Statin use was unrestricted, and 597 subjects (21.2% overall; 332 [20.2%] tolvaptan, 265 [22.6%] placebo) received statins. Statin use (duration, dose change, statin change, permanent discontinuation), incidences of statin-related adverse events, and hepatic transaminase elevations were determined for subjects who received tolvaptan+statin, placebo+statin, tolvaptan alone, and placebo alone. RESULTS: No differences in statin use parameters between tolvaptan- and placebo-treated subjects were observed. No statistically significant increases in commonly reported statin-related adverse events (e.g., musculoskeletal disorders, gastrointestinal symptoms) were seen between subjects receiving tolvaptan+statin and placebo+statin. For example, in TEMPO 3:4, frequencies were 5.4% and 7.8%, respectively, for myalgia (difference -2.4%; 95% confidence interval, -11.2% to 6.4%) and 9.3% and 7.8%, respectively, for abdominal pain (difference 1.5%; -7.9% to 10.9%). In an analysis that excluded participants concurrently using allopurinol, the frequency of alanine transaminase or aspartate transaminase >3× upper limit of normal in the pooled study populations was 3.6% for the tolvaptan+statin group and 2.3% for the placebo+statin group (difference 1.4%; -2.0% to 4.7%). CONCLUSIONS: Tolvaptan has been used safely in combination with statins in clinical trials. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_04_06_CJN.08170719.mp3.

Multicenter Study of Long-Term Safety of Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND AND OBJECTIVES: Tolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. In the 3-year Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4, 2-year extension to TEMPO 3:4 (TEMPO 4:4), and 1-year Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trials, aquaretic adverse events were common. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations occurred in all three studies. Three patients met Hy Law criteria (ALT or AST more than three times and total bilirubin more than two times the upper limit of normal) for severe drug-induced liver injury (two in TEMPO 3:4 and one in TEMPO 4:4). In REPRISE, liver enzyme monitoring frequency was increased to monthly, with no Hy Law cases. A long-term, phase 3 safety study has further characterized tolvaptan safety. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Subjects who completed TEMPO 4:4, REPRISE, or other tolvaptan trials could enroll in this prospective, multinational, open-label safety study. Assessments included monthly liver enzyme testing during the first 18 months of tolvaptan exposure and every 3 months thereafter. RESULTS: Among 1803 subjects, median tolvaptan exposure during the extension was 651 days (interquartile range, 538-924), and cumulative exposure (extension and previous trials) was ≤11 years. Subjects entering from REPRISE placebo experienced more aquaretic adverse events compared with subjects from TEMPO 4:4 or REPRISE tolvaptan (i.e., patients with prior long-term tolvaptan exposure). Liver enzyme elevations also occurred more frequently in subjects from REPRISE placebo. Percentages experiencing ALT ≥3/≥5/ ≥10/≥20 times the upper limit of normal were 3.2%/2.1%/0.9%/0.7%, respectively, in subjects from REPRISE placebo and 0.6%-1.1%/0.0%-0.1%/0%/0%, respectively, in those from REPRISE tolvaptan and TEMPO 4:4. Percentages experiencing AST ≥3/ ≥5/≥10/≥20 times the upper limit of normal were 6.9%/3.8%/2.3%/0.8%, respectively, in subjects from REPRISE placebo and 0.9%-2.0%/0.0%-1.0%/0%/0%, respectively, in those from REPRISE tolvaptan and TEMPO 4:4. No Hy Law cases occurred. CONCLUSIONS: No new safety signals emerged during this long-term extension. Monthly liver function testing for the first 18 months of treatment appeared to enable effective detection and management of transaminase elevations. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Open Label Extension of TEMPO 3:4, NCT02251275.