Altered Hepatobiliary Disposition of Tolvaptan and Selected Tolvaptan Metabolites in a Rodent Model of Polycystic Kidney Disease

Abstract

Tolvaptan, a vasopressin V 2 -receptor antagonist, has demonstrated efficacy in slowing kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD). In the pivotal clinical trial, the incidence of elevated liver enzymes was higher in patients receiving tolvaptan compared with placebo. Adjudication by a panel of expert hepatologists concluded a causal link of tolvaptan to liver injury in patients with ADPKD. An ex situ isolated perfused liver (IPL) study of tolvaptan disposition was undertaken in a rodent model of ADPKD, the polycystic kidney (PCK) rat (n = 5), and compared with wild-type (WT) Sprague-Dawley rats (n = 6). Livers were perfused with tolvaptan, followed by a tolvaptan-free washout phase. Total recovery (mean 6 S.D. percentage of dose; PCK vs. WT) of tolvaptan and two metabolites, DM-4103 and DM-4107, quantified by liquid chromatography-tandem mass spectroscopy, was 58.14% 6 24.72% vs. 43.40% 6 18.11% in liver, 20.10% 6 9.15% vs. 21.17% 6 12.51% in outflow perfusate, and 0.08% 6 0.01% vs. 0.39% 6 0.32% in bile. DM-4103 recovery (mean 6 S.D. percentage of dose) was decreased in PCK vs. WT bile (<0.01% 6 <0.01% vs. 0.02% 6 0.01%; P = 0.0037), and DM-4107 recovery was increased in PCK vs. WT outflow perfusate (1.60% 6 0.57% vs. 0.43% 6 0.29%; P = 0.0017). A pharmacokinetic compartmental model assuming first-order processes was developed to describe the rate vs. time profiles of tolvaptan and DM-4103 + DM-4107 in rat IPLs. The model-derived estimate of tolvaptan's biliary clearance was significantly decreased in PCK compared with WT IPLs. The model predicted greater hepatocellular concentrations of tolvaptan and DM-4103 + DM-4107 in PCK compared with WT IPLs. Increased hepatocellular exposure to tolvaptan and metabolites may contribute to the hepatotoxicity in patients with ADPKD treated with tolvaptan.

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

“…Patients with ADPKD may be susceptible to altered hepatobiliary disposition of tolvaptan and metabolites, similar to what has been observed in PCK rats 22 . This may contribute to the apparent ADPKD‐specific susceptibility to tolvaptan‐associated hepatotoxicity.…”

“…18 In addition, DM-4103 biliary recovery is significantly reduced in PCK compared with control rat livers perfused with tolvaptan. 22 Patients with ADPKD may be susceptible to altered hepatobiliary disposition of tolvaptan and metabolites, similar to what has been observed in PCK rats. 22 This may contribute to the apparent ADPKD-specific susceptibility to tolvaptan-associated hepatotoxicity.…”

“…22 Patients with ADPKD may be susceptible to altered hepatobiliary disposition of tolvaptan and metabolites, similar to what has been observed in PCK rats. 22 This may contribute to the apparent ADPKD-specific susceptibility to tolvaptan-associated hepatotoxicity. Because changes in bile acid homeostasis are believed to play a role in tolvaptan-associated hepatotoxicity in patients, 19 and because rats have a bile acid profile different from humans, [23][24][25] quantitative systems toxicology (QST) modeling is an ideal approach to test this hypothesis for tolvaptan.…”

“…DM‐4103 inhibits MRP2 (IC 50 = 51.0 µM) 18 . In addition, DM‐4103 biliary recovery is significantly reduced in PCK compared with control rat livers perfused with tolvaptan 22 …”

Altered Expression and Function of Hepatic Transporters in a Rodent Model of Polycystic Kidney Disease

“…In addition, serum bilirubin concentrations are increased in PCK rats, suggesting impaired Mrp2 function (Mason et al, 2010;Shimomura et al, 2015). Furthermore, the biliary clearance of tolvaptan was significantly decreased in isolated perfused livers (IPLs) from PCK rats compared with wild-type (WT) rats (Beaudoin et al, 2019). The IPL is a physiologically relevant ex situ model (Brouwer and Thurman, 1996) that has been used to evaluate the hepatic transport and metabolic properties of various compounds (Chandra et al, 2005a;Miranda et al, 2008;Pfeifer et al, 2013).…”