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

Watkins, Paul B.; Lewis, James H.; Kaplowitz, Neil; Alpers, David H.; Blais, Jaime D.; M., Smotzer, Dan; Krasa, Holly B.; Ouyang, John; Torres, Vicente E.; Czerwiec, Frank S.; Zimmer, Christopher

doi:10.1007/s40264-015-0327-3

Cited by 160 publications

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“…Two patients in the TEMPO 3:4 trial and one in the TEMPO 4:4 study, which used monitoring once every 4 months, had laboratory and clinical evidence of potentially serious druginduced liver injury, meeting Hy's law criteria (serum alanine aminotransferase level of >3 times the upper limit of the normal range and bilirubin level of >2 times the upper limit of the normal range). 18 In the present trial, in which monthly monitoring was used, no cases of elevations in the liver-enzyme and bilirubin levels met Hy's law criteria; this finding is possibly due to more frequent monitoring and earlier interruption of therapy.…”

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confidence: 48%

“…17 Idiosyncratic hepatocellular toxic effects were unanticipated. 18 With monitoring occurring once every 4 months, two patients in the TEMPO 3:4 trial and one in the TEMPO 4:4 study had evidence of potentially serious drug-induced liver injury. We conducted the Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trial, a phase 3, randomized withdrawal, multicenter, placebocontrolled, double-blind trial involving patients with ADPKD who had late chronic kidney disease of stage 2 to early stage 4, in order to ascertain the efficacy and safety of tolvaptan in patients with more advanced ADPKD with the use of more frequent monitoring for toxic effects in the liver.…”

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Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

et al. 2017

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BACKGROUNDIn a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, ≥60 ml per minute), the vasopressin V 2 -receptor antagonist tolvaptan slowed the growth in total kidney volume and the decline in the estimated glomerular filtration rate (GFR) but also caused more elevations in aminotransferase and bilirubin levels. The efficacy and safety of tolvaptan in patients with later-stage ADPKD are unknown. METHODSWe conducted a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial. After an 8-week prerandomization period that included sequential placebo and tolvaptan run-in phases, during which each patient's ability to take tolvaptan without dose-limiting side effects was assessed, 1370 patients with ADPKD who were either 18 to 55 years of age with an estimated GFR of 25 to 65 ml per minute per 1.73 m 2 of body-surface area or 56 to 65 years of age with an estimated GFR of 25 to 44 ml per minute per 1.73 m 2 were randomly assigned in a 1:1 ratio to receive tolvaptan or placebo for 12 months. The primary end point was the change in the estimated GFR from baseline to follow-up, with adjustment for the exact duration that each patient participated (interpolated to 1 year). Safety assessments were conducted monthly. RESULTSThe change from baseline in the estimated GFR was −2.34 ml per minute per 1.73 m 2 (95% confidence interval [CI], −2.81 to −1.87) in the tolvaptan group, as compared with −3.61 ml per minute per 1.73 m 2 (95% CI, −4.08 to −3.14) in the placebo group (difference, 1.27 ml per minute per 1.73 m 2 ; 95% CI, 0.86 to 1.68; P<0.001). Elevations in the alanine aminotransferase level (to >3 times the upper limit of the normal range) occurred in 38 of 681 patients (5.6%) in the tolvaptan group and in 8 of 685 (1.2%) in the placebo group. Elevations in the aminotransferase level were reversible after stopping tolvaptan. No elevations in the bilirubin level of more than twice the upper limit of the normal range were detected. CONCLUSIONSTolvaptan resulted in a slower decline than placebo in the estimated GFR over a 1-year period in patients with later-stage ADPKD. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; REPRISE ClinicalTrials.gov number, NCT02160145.)

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Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

et al. 2017

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“…The only laboratory abnormality that occurred more frequently in tolvaptan-treated patient and that was affected by CKD stage was hypernatremia, defined as an elevation of plasma sodium $150 mEq/L. Recently, an independent, blinded, expert hepatic adjudication committee examined data from TEMPO 3:4 using the five-point Drug-Induced Liver Injury Network classification and identified 16 tolvaptan-treated patients who experienced aminotransferase elevations that were deemed to be probably or highly likely due to study drug (26). Five of patients with CKD3 (3.1%) had an adjudicated hepatic event versus six patients with CKD1 (1.8%) and five with CKD2 (1.1%) (26).…”

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confidence: 99%

“…Recently, an independent, blinded, expert hepatic adjudication committee examined data from TEMPO 3:4 using the five-point Drug-Induced Liver Injury Network classification and identified 16 tolvaptan-treated patients who experienced aminotransferase elevations that were deemed to be probably or highly likely due to study drug (26). Five of patients with CKD3 (3.1%) had an adjudicated hepatic event versus six patients with CKD1 (1.8%) and five with CKD2 (1.1%) (26). The analysis presented here is post hoc, carrying the risk of a false-positive result, and should serve as hypothesis generating.…”

Section: Discussionmentioning

confidence: 99%

“…This is a post hoc, exploratory analysis of the TEMPO 3:4 trial (13,18) (ClinicalTrials.gov identifier: NCT00428948, January 26,2007). Eligibility requirements included a diagnosis of ADPKD, a total kidney volume of $750 ml as measured by magnetic resonance imaging (MRI), a creatinine clearance of $60 ml/min as estimated by the CockcroftGault formula and an age of 18-50 years.…”

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Effect of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease by CKD Stage: Results from the TEMPO 3:4 Trial

Torres¹,

Higashihara²,

Devuyst³

et al. 2016

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Background and objectives The Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 study demonstrated a significant beneficial effect of the vasopressin V2 receptor antagonist tolvaptan on rates of kidney growth and eGFR decline in autosomal dominant polycystic kidney disease (ADPKD). This post hoc analysis was performed to reassess the primary and secondary efficacy endpoints by CKD stage at baseline.Design, setting, participants, & measurements In a phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, 1445 patients with ADPKD (age 18-50 years), with total kidney volume (TKV) $750 ml and estimated creatinine clearance $60 ml/min, were randomly assigned 2:1 to split-dose tolvaptan (45/15, 60/30, or 90/30 mg daily as tolerated) or placebo. The primary endpoint was annualized rate of TKV change. Secondary endpoints included a composite endpoint of time to multiple composite ADPKD-related events (worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney function decline.Results Tolvaptan reduced annualized TKV growth by 1.99%, 3.12%, and 2.61% per year (all P,0.001; subgrouptreatment interaction, P=0.17) and eGFR decline by 0.40 in CKD1 (P=0.23), 1.13 in CKD2 (P,0.001) and 1.66 ml/min per 1.73 m 2 per year in CKD3 (P,0.001) with a trend for a positive subgroup-treatment interaction (P=0.07) across CKD1, CKD2 and CKD3. ADPKD-related events were less frequent in tolvaptan recipients than in placebo recipients among those with CKD1 (hazard ratio [HR], 0.83; 95% confidence interval [95% CI], 0.70-0.98; P=0.03) and those with CKD 3 (HR, 0.71; 95% CI, 0.57-0.89; P=0.003), but not among those with CKD2 (HR, 1.02; 95% CI, 0.85-1.21; P=0.86). Aquaresis-related adverse events (more frequent in the tolvaptan group) and ADPKD-related adverse events (more frequent in the placebo group) were not associated with CKD stage. Hypernatremia events in tolvaptan-treated patients with CKD3 and plasma aminotransferase elevations in tolvaptan-treated patients across CKD stages 1-3 occurred more frequently than in placebo recipients.Conclusions This post hoc analysis suggests clinically similar beneficial effects of tolvaptan in ADPKD across CKD stages 1-3.

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Quantitative Systems Toxicology Modeling Predicts that Reduced Biliary Efflux Contributes to Tolvaptan Hepatotoxicity

Beaudoin

Brock

Watkins

et al. 2020

Clin Pharma and Therapeutics

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Patients with autosomal dominant polycystic kidney disease (ADPKD) exhibit enhanced susceptibility to tolvaptan hepatotoxicity relative to other patient populations. In a rodent model of ADPKD, the expression and function of the biliary efflux transporter Mrp2 was reduced, and biliary excretion of a major tolvaptan metabolite (DM‐4103) was decreased. The current study investigated whether reduced biliary efflux could contribute to increased susceptibility to tolvaptan‐associated hepatotoxicity using a quantitative systems toxicology (QST) model (DILIsym). QST simulations revealed that decreased biliary excretion of DM‐4103, but not tolvaptan, resulted in substantial hepatic accumulation of bile acids, decreased electron transport chain activity, reduced hepatic adenosine triphosphate concentrations, and an increased incidence of hepatotoxicity. In vitro experiments (C‐DILI) with sandwich‐cultured human hepatocytes and HepaRG cells were performed to assess tolvaptan‐associated hepatotoxic effects when MRP2 was impaired by chemical inhibition (MK571, 50 µM) or genetic knockout, respectively. Tolvaptan (64 µM, 24‐hour) treatment of these cells increased cytotoxicity markers up to 27.9‐fold and 1.6‐fold, respectively, when MRP2 was impaired, indicating that MRP2 dysfunction may be involved in tolvaptan‐associated cytotoxicity. In conclusion, QST modeling supported the hypothesis that reduced biliary efflux of tolvaptan and/or DM‐4103 could account for increased susceptibility to tolvaptan‐associated hepatotoxicity; in vitro experiments implicated MRP2 dysfunction as a key factor in susceptibility. QST simulations revealed that DM‐4103 may contribute to hepatotoxicity more than the parent compound. ADPKD progression and gradual reduction in MRP2 activity may explain why acute liver events can occur well after one year of tolvaptan treatment.

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

Cited by 160 publications

References 20 publications

Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

Effect of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease by CKD Stage: Results from the TEMPO 3:4 Trial

Quantitative Systems Toxicology Modeling Predicts that Reduced Biliary Efflux Contributes to Tolvaptan Hepatotoxicity

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