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Kim L. R. Brouwer - One of the best experts on this subject based on the ideXlab platform.
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altered hepatobiliary disposition of Tolvaptan and selected Tolvaptan metabolites in a rodent model of polycystic kidney disease
Drug Metabolism and Disposition, 2019Co-Authors: James J Beaudoin, William J. Brock, Jacqueline Bezencon, Yanguang Cao, Katsuhiko Mizuno, Sharin E Roth, Kim L. R. BrouwerAbstract:Tolvaptan, a vasopressin V2-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 ± 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% ± 24.72% vs. 43.40% ± 18.11% in liver, 20.10% ± 9.15% vs. 21.17% ± 12.51% in outflow perfusate, and 0.08% ± 0.01% vs. 0.39% ± 0.32% in bile. DM-4103 recovery (mean ± S.D. percentage of dose) was decreased in PCK vs. WT bile (<0.01% ± <0.01% vs. 0.02% ± 0.01%; P = 0.0037), and DM-4107 recovery was increased in PCK vs. WT outflow perfusate (1.60% ± 0.57% vs. 0.43% ± 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.
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altered hepatobiliary disposition of Tolvaptan and selected Tolvaptan metabolites in a rodent model of polycystic kidney disease
Drug Metabolism and Disposition, 2019Co-Authors: James J Beaudoin, William J. Brock, Jacqueline Bezencon, Katsuhiko Mizuno, Sharin E Roth, Kim L. R. BrouwerAbstract:Tolvaptan, a vasopressin V2-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 ± 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% ± 24.72% vs. 43.40% ± 18.11% in liver, 20.10% ± 9.15% vs. 21.17% ± 12.51% in outflow perfusate, and 0.08% ± 0.01% vs. 0.39% ± 0.32% in bile. DM-4103 recovery (mean ± S.D. percentage of dose) was decreased in PCK vs. WT bile (
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application of a mechanistic model to evaluate putative mechanisms of Tolvaptan drug induced liver injury and identify patient susceptibility factors
Toxicological Sciences, 2017Co-Authors: Jeffrey L Woodhead, William J. Brock, Kim L. R. Brouwer, Susan E. Shoaf, Sharin E Roth, Rachel J Church, Tom N Grammatopoulos, Linsey Stiles, Scott Q Siler, Brett A HowellAbstract:Tolvaptan is a selective vasopressin V2 receptor antagonist, approved in several countries for the treatment of hyponatremia and autosomal dominant polycystic kidney disease (ADPKD). No liver injury has been observed with Tolvaptan treatment in healthy subjects and in non-ADPKD indications, but ADPKD clinical trials showed evidence of drug-induced liver injury (DILI). Although all DILI events resolved, additional monitoring in Tolvaptan-treated ADPKD patients is required. In vitro assays identified alterations in bile acid disposition and inhibition of mitochondrial respiration as potential mechanisms underlying Tolvaptan hepatotoxicity. This report details the application of DILIsym software to determine whether these mechanisms could account for the liver safety profile of Tolvaptan observed in ADPKD clinical trials. DILIsym simulations included physiologically based pharmacokinetic estimates of hepatic exposure for Tolvaptan and2 metabolites, and their effects on hepatocyte bile acid transporters and mitochondrial respiration. The frequency of predicted alanine aminotransferase (ALT) elevations, following simulated 90/30 mg split daily dosing, was 7.9% compared with clinical observations of 4.4% in ADPKD trials. Toxicity was multifactorial as inhibition of bile acid transporters and mitochondrial respiration contributed to the simulated DILI. Furthermore, simulation analysis identified both pre-treatment risk factors and on-treatment biomarkers predictive of simulated DILI. The simulations demonstrated that in vivo hepatic exposure to Tolvaptan and the DM-4103 metabolite, combined with these 2 mechanisms of toxicity, were sufficient to account for the initiation of Tolvaptan-mediated DILI. Identification of putative risk-factors and potential novel biomarkers provided insight for the development of mechanism-based Tolvaptan risk-mitigation strategies.
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Hepatocellular Disposition and Transporter Interactions with Tolvaptan and Metabolites in Sandwich-Cultured Human Hepatocytes
Drug Metabolism and Disposition, 2016Co-Authors: Yang Lu, Jason R. Slizgi, Robert L. St. Claire, Kimberly M. Freeman, William J. Brock, Kenneth R Brouwer, Kim L. R. BrouwerAbstract:Tolvaptan is a selective V2-receptor antagonist primarily metabolized by CYP 3A. The present study investigated the hepatocellular disposition of Tolvaptan and the generated Tolvaptan metabolites, DM-4103 and DM-4107, as well as the potential for drug-drug interactions (DDIs) with metabolic and transport proteins in sandwich-cultured human hepatocytes (SCHH). Tolvaptan was incubated with SCHH and quantified by liquid chromatography–tandem mass spectrometry. Pioglitazone, verapamil, MK-571, and elacridar were used as inhibitors to investigate mechanisms of transport and metabolism of Tolvaptan and metabolites. Taurocholate (TCA), pravastatin, digoxin, and metformin were used as transporter probes to investigate which transport proteins were inhibited by Tolvaptan and metabolites. Cellular accumulation of Tolvaptan (0.15–50 μ M), DM-4103, and DM-4107 in SCHH was concentration-dependent. Tolvaptan accumulation (15 μ M) in SCHH was not altered markedly by 50 μ M pioglitazone, verapamil, MK-571, or 10 μ M elacridar. Coincubation of Tolvaptan with pioglitazone, verapamil, MK-571, and elacridar reduced DM-4107 accumulation by 45.6, 79.8, 94.5, and 23.0%, respectively, relative to control. Coincubation with increasing Tolvaptan concentrations (0.15–50 μ M) decreased TCA (2.5 μ M) cell+bile accumulation and the TCA biliary excretion index (BEI; from 76% to 51%), consistent with inhibition of the bile salt export pump (BSEP). Tolvaptan (15 μ M) had no effect on the cellular accumulation of 2.5 μ M pravastatin or metformin. Digoxin cellular accumulation increased, and the BEI of digoxin decreased from 23.9 to 8.1% in the presence of 15 μ M Tolvaptan, consistent with inhibition of P-glycoprotein. In summary, SCHH studies revealed potential metabolic- and transporter-mediated DDIs involving Tolvaptan and metabolites.
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Hepatocellular Disposition and Transporter Interactions with Tolvaptan and Metabolites in Sandwich-Cultured Human Hepatocytes.
Drug metabolism and disposition: the biological fate of chemicals, 2016Co-Authors: Jason R. Slizgi, Robert L. St. Claire, Kimberly M. Freeman, William J. Brock, Kenneth R Brouwer, Maxwell Pan, Kim L. R. BrouwerAbstract:Tolvaptan is a selective V2-receptor antagonist primarily metabolized by CYP3A. The present study investigated the hepatocellular disposition of Tolvaptan and the generated Tolvaptan metabolites, DM-4103 and DM-4107, as well as the potential for drug-drug interaction (DDIs) with metabolic and transport proteins in sandwich-cultured human hepatocytes (SCHH). Tolvaptan was incubated with SCHH and quantified by LC-MS/MS. Pioglitazone, verapamil, MK-571 and elacridar were used as inhibitors to investigate mechanisms of transport and metabolism of Tolvaptan and metabolites. Taurocholate (TCA), pravastatin, digoxin, and metformin were used as transporter probes to investigate which transport proteins were inhibited by Tolvaptan and metabolites. Cellular accumulation of Tolvaptan (0.15-50 μM), DM-4103 and DM-4107 in SCHH was concentration dependent. Tolvaptan accumulation (15 μM) in SCHH was not altered markedly by 50 μM pioglitazone, verapamil or MK-571, or 10 μM elacridar. Co-incubation of Tolvaptan with pioglitazone, verapamil, MK-571 and elacridar reduced DM-4107 accumulation by 45.6, 79.8, 94.5 and 23.0%, respectively, relative to control. Co-incubation with increasing Tolvaptan concentrations (0.15-50 μM) decreased TCA (2.5 μM) cell+bile accumulation and the TCA biliary excretion index (BEI; from 76% to 51%), consistent with inhibition of the bile salt export pump (BSEP). Tolvaptan (15 μM) had no effect on the cellular accumulation of 2.5 μM pravastatin or metformin. Digoxin cellular accumulation increased and the BEI of digoxin decreased from 23.9% to 8.1% in the presence of 15 μM Tolvaptan, consistent with inhibition of P-glycoprotein (P-gp). In summary, SCHH studies revealed potential metabolic- and transporter-mediated DDIs involving Tolvaptan and metabolites.
Frank S. Czerwiec - One of the best experts on this subject based on the ideXlab platform.
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The NOCTURNE Randomized Trial Comparing 2 Tolvaptan Formulations.
Kidney international reports, 2020Co-Authors: Ronald D. Perrone, Arlene B. Chapman, John Ouyang, Frank S. Czerwiec, Dorothee Oberdhan, Olga Sergeyeva, Susan E. ShoafAbstract:Introduction Tolvaptan, a treatment for autosomal dominant polycystic kidney disease (ADPKD), inhibits vasopressin V2 receptor signaling, which causes aquaretic adverse events (AAEs). The short-term efficacy and tolerability of a once-daily, modified-release (MR) formulation was assessed relative to the twice-daily, immediate-release (IR) formulation. Methods This Phase 2 multicenter, randomized (1:1:1:1), placebo-controlled, double-blind, placebo-masked, parallel-group study (NCT01451827) compared Tolvaptan MR 50 mg once daily or Tolvaptan MR 80 mg once daily with Tolvaptan IR 60/30 mg daily split dose and placebo over 8 weeks in 177 subjects. The primary endpoint was percent change from baseline in total kidney volume (TKV) at week 3. Other endpoints included tolerability, assessed by adverse events and quality of life (QOL) measures. Results Mean percentage decreases in TKV at week 3 were observed for the pooled group of all (MR+IR) Tolvaptan-treated subjects (−2.07%), Tolvaptan MR 80 mg (−2.55%), and Tolvaptan MR 50 mg (−2.46%) versus placebo (0.09%; P Conclusion Tolvaptan MR and Tolvaptan IR demonstrated similar short-term efficacy, tolerability, and safety, with low impact on multiple measures of QOL. Conclusions regarding long-term efficacy are limited by the short duration of follow-up.
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tolerability of aquaretic related symptoms following Tolvaptan for autosomal dominant polycystic kidney disease results from tempo 3 4
Kidney International Reports, 2017Co-Authors: Olivier Devuyst, Arlene B. Chapman, Frank S. Czerwiec, Susan E. Shoaf, Jaime D. BlaisAbstract:Introduction In the randomized placebo-controlled Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial, Tolvaptan slowed kidney growth and renal function decline in subjects with autosomal dominant polycystic kidney disease (ADPKD). Consistent with its primary pharmacologic activity, Tolvaptan use was commonly associated with aquaretic adverse events (AAEs) attributable to excess free water clearance. Methods A post hoc analysis of Tolvaptan-related discontinuations from the pivotal randomized controlled trial TEMPO 3:4 and its open-label extension TEMPO 4:4. Results In total, 750 of 961 Tolvaptan-treated subjects (78%) in TEMPO 3:4 reported at least one AAE. Of these 750 subjects, 72 (10%) discontinued because of an AAE (aquaretic-discontinued group) and 573 (76%) continued (aquaretic-continued group). The aquaretic-discontinued subjects were younger, had better baseline renal function, and had higher fasting urine osmolality than aquaretic-continued subjects. Of the 750 subjects reporting an AAE, 105 (14%) discontinued for another reason (non-aquaretic-discontinued group). Compared to non-aquaretic-discontinued subjects, aquaretic-discontinued subjects were more commonly male, had better baseline renal function, and discontinued the study drug faster. After 3 years of therapy, 75% of Tolvaptan subjects indicated that they could tolerate their current dose for the rest of their lives, compared to 85% of placebo subjects. These findings were corroborated by results in the open-label extension trial TEMPO 4:4. Discussion In this study, AAEs were common but well tolerated in ADPKD patients on Tolvaptan. ADPKD patients in earlier stages of disease progression may be more sensitive to aquaretic symptoms, which may help in guiding Tolvaptan dosing and titration decisions in the future.
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Urine Osmolality, Response to Tolvaptan, and Outcome in Autosomal Dominant Polycystic Kidney Disease: Results from the TEMPO 3:4 Trial
Journal of the American Society of Nephrology, 2016Co-Authors: Olivier Devuyst, Arlene B. Chapman, Ron T. Gansevoort, Eiji Higashihara, Ronald D. Perrone, Vicente E. Torres, Jaime D. Blais, Wen Zhou, John Ouyang, Frank S. CzerwiecAbstract:The vasopressin-cAMP-osmolality axis is abnormal in autosomal dominant polycystic kidney disease (ADPKD). In the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 Trial, a 3-year randomized, placebo-controlled trial in adults, the vasopressin V2 receptor antagonist Tolvaptan slowed ADPKD progression in patients with preserved GFR. Here, we investigated the determinants of baseline urine osmolality (Uosm) and its value as a severity marker of ADPKD, the factors influencing the response to Tolvaptan, and whether change in Uosm associated with key trial end points. At baseline, lower Uosm independently associated with female sex, presence of hypertension, lower eGFR, higher total kidney volume (TKV), and higher age. Tolvaptan consistently reduced Uosm by 200-300 mOsm/kg over 36 months. The Uosm response to Tolvaptan depended on baseline eGFR and Uosm. Subjects with greater change in Uosm experienced a significant reduction in clinical progression events. Among subjects receiving Tolvaptan, those with a greater suppression of Uosm had slower renal function decline. Assessment at follow-up, off medication, revealed a significant decrease in Uosm in both placebo and treated groups. Tolvaptan significantly increased plasma osmolality, which returned to baseline at follow-up. In conclusion, baseline Uosm in ADPKD reflects age, renal function, and TKV, and baseline Uosm, eGFR, and TKV influence the effect of Tolvaptan on Uosm. The greatest renal benefit occurred in subjects achieving greater suppression of Uosm, that is, those with better eGFR at baseline. These results support the link between vasopressin V2 receptor signaling and ADPKD progression.
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Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database
Drug Safety, 2015Co-Authors: Paul B. Watkins, Vicente E. Torres, Jaime D. Blais, John Ouyang, James H. Lewis, Neil Kaplowitz, David H. Alpers, Dan M. Smotzer, Holly Krasa, Frank S. CzerwiecAbstract: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.
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short term renal hemodynamic effects of Tolvaptan in subjects with autosomal dominant polycystic kidney disease at various stages of chronic kidney disease
Kidney International, 2013Co-Authors: Wendy E Boertien, Frank S. Czerwiec, Susan E. Shoaf, Dorothee Oberdhan, Holly B Krasa, Esther Meijer, Paul E De Jong, Stephan J L Bakker, Joachim Struck, Ron T. GansevoortAbstract:Vasopressin V2-receptor antagonists may delay disease progression in ADPKD. Trials with V2-receptor antagonists have been performed predominantly in patients with an estimated creatinine clearance of 60ml/min or more. Here we determined renal hemodynamic effects of the V2-receptor antagonist Tolvaptan in 27 patients with ADPKD at various stages of chronic kidney disease: group A: >60, group B: 30–60, and group C: 2 . Measurements were performed before, after 3 weeks of Tolvaptan (up titration to 90/30mg/day, split dose), and 3 weeks after the last dose of Tolvaptan. With Tolvaptan, a minor, reversible decrease in GFR ( 125 I-iothalamate clearance) was found that reached significance in groups A and B: –7.8 (interquartile range –13.7 to –1.3) and –4.3 (–9.7 to –0.9) ml/min per 1.73m 2 , respectively, but not in group C (GFR decrease –0.7 (–1.1 to 1.5) ml/min/1.73m 2 ). The percentage change in GFR, ERPF ( 131 I-hippuran clearance), and filtration fraction with Tolvaptan did not differ between the three study groups. No differences between the three study groups were found in other main efficacy variables, besides smaller increases in urine volume in group C during Tolvaptan treatment. Tolvaptan was well tolerated, with only two patients withdrawing. Thus, doses of Tolvaptan typically used in patients with ADPKD do not produce a difference in renal hemodynamic profile in chronic kidney disease stages 1 through 4, but minor GFR drops may be observed in individual patients.
Susan E. Shoaf - One of the best experts on this subject based on the ideXlab platform.
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The NOCTURNE Randomized Trial Comparing 2 Tolvaptan Formulations.
Kidney international reports, 2020Co-Authors: Ronald D. Perrone, Arlene B. Chapman, John Ouyang, Frank S. Czerwiec, Dorothee Oberdhan, Olga Sergeyeva, Susan E. ShoafAbstract:Introduction Tolvaptan, a treatment for autosomal dominant polycystic kidney disease (ADPKD), inhibits vasopressin V2 receptor signaling, which causes aquaretic adverse events (AAEs). The short-term efficacy and tolerability of a once-daily, modified-release (MR) formulation was assessed relative to the twice-daily, immediate-release (IR) formulation. Methods This Phase 2 multicenter, randomized (1:1:1:1), placebo-controlled, double-blind, placebo-masked, parallel-group study (NCT01451827) compared Tolvaptan MR 50 mg once daily or Tolvaptan MR 80 mg once daily with Tolvaptan IR 60/30 mg daily split dose and placebo over 8 weeks in 177 subjects. The primary endpoint was percent change from baseline in total kidney volume (TKV) at week 3. Other endpoints included tolerability, assessed by adverse events and quality of life (QOL) measures. Results Mean percentage decreases in TKV at week 3 were observed for the pooled group of all (MR+IR) Tolvaptan-treated subjects (−2.07%), Tolvaptan MR 80 mg (−2.55%), and Tolvaptan MR 50 mg (−2.46%) versus placebo (0.09%; P Conclusion Tolvaptan MR and Tolvaptan IR demonstrated similar short-term efficacy, tolerability, and safety, with low impact on multiple measures of QOL. Conclusions regarding long-term efficacy are limited by the short duration of follow-up.
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tolerability of aquaretic related symptoms following Tolvaptan for autosomal dominant polycystic kidney disease results from tempo 3 4
Kidney International Reports, 2017Co-Authors: Olivier Devuyst, Arlene B. Chapman, Frank S. Czerwiec, Susan E. Shoaf, Jaime D. BlaisAbstract:Introduction In the randomized placebo-controlled Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial, Tolvaptan slowed kidney growth and renal function decline in subjects with autosomal dominant polycystic kidney disease (ADPKD). Consistent with its primary pharmacologic activity, Tolvaptan use was commonly associated with aquaretic adverse events (AAEs) attributable to excess free water clearance. Methods A post hoc analysis of Tolvaptan-related discontinuations from the pivotal randomized controlled trial TEMPO 3:4 and its open-label extension TEMPO 4:4. Results In total, 750 of 961 Tolvaptan-treated subjects (78%) in TEMPO 3:4 reported at least one AAE. Of these 750 subjects, 72 (10%) discontinued because of an AAE (aquaretic-discontinued group) and 573 (76%) continued (aquaretic-continued group). The aquaretic-discontinued subjects were younger, had better baseline renal function, and had higher fasting urine osmolality than aquaretic-continued subjects. Of the 750 subjects reporting an AAE, 105 (14%) discontinued for another reason (non-aquaretic-discontinued group). Compared to non-aquaretic-discontinued subjects, aquaretic-discontinued subjects were more commonly male, had better baseline renal function, and discontinued the study drug faster. After 3 years of therapy, 75% of Tolvaptan subjects indicated that they could tolerate their current dose for the rest of their lives, compared to 85% of placebo subjects. These findings were corroborated by results in the open-label extension trial TEMPO 4:4. Discussion In this study, AAEs were common but well tolerated in ADPKD patients on Tolvaptan. ADPKD patients in earlier stages of disease progression may be more sensitive to aquaretic symptoms, which may help in guiding Tolvaptan dosing and titration decisions in the future.
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application of a mechanistic model to evaluate putative mechanisms of Tolvaptan drug induced liver injury and identify patient susceptibility factors
Toxicological Sciences, 2017Co-Authors: Jeffrey L Woodhead, William J. Brock, Kim L. R. Brouwer, Susan E. Shoaf, Sharin E Roth, Rachel J Church, Tom N Grammatopoulos, Linsey Stiles, Scott Q Siler, Brett A HowellAbstract:Tolvaptan is a selective vasopressin V2 receptor antagonist, approved in several countries for the treatment of hyponatremia and autosomal dominant polycystic kidney disease (ADPKD). No liver injury has been observed with Tolvaptan treatment in healthy subjects and in non-ADPKD indications, but ADPKD clinical trials showed evidence of drug-induced liver injury (DILI). Although all DILI events resolved, additional monitoring in Tolvaptan-treated ADPKD patients is required. In vitro assays identified alterations in bile acid disposition and inhibition of mitochondrial respiration as potential mechanisms underlying Tolvaptan hepatotoxicity. This report details the application of DILIsym software to determine whether these mechanisms could account for the liver safety profile of Tolvaptan observed in ADPKD clinical trials. DILIsym simulations included physiologically based pharmacokinetic estimates of hepatic exposure for Tolvaptan and2 metabolites, and their effects on hepatocyte bile acid transporters and mitochondrial respiration. The frequency of predicted alanine aminotransferase (ALT) elevations, following simulated 90/30 mg split daily dosing, was 7.9% compared with clinical observations of 4.4% in ADPKD trials. Toxicity was multifactorial as inhibition of bile acid transporters and mitochondrial respiration contributed to the simulated DILI. Furthermore, simulation analysis identified both pre-treatment risk factors and on-treatment biomarkers predictive of simulated DILI. The simulations demonstrated that in vivo hepatic exposure to Tolvaptan and the DM-4103 metabolite, combined with these 2 mechanisms of toxicity, were sufficient to account for the initiation of Tolvaptan-mediated DILI. Identification of putative risk-factors and potential novel biomarkers provided insight for the development of mechanism-based Tolvaptan risk-mitigation strategies.
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short term renal hemodynamic effects of Tolvaptan in subjects with autosomal dominant polycystic kidney disease at various stages of chronic kidney disease
Kidney International, 2013Co-Authors: Wendy E Boertien, Frank S. Czerwiec, Susan E. Shoaf, Dorothee Oberdhan, Holly B Krasa, Esther Meijer, Paul E De Jong, Stephan J L Bakker, Joachim Struck, Ron T. GansevoortAbstract:Vasopressin V2-receptor antagonists may delay disease progression in ADPKD. Trials with V2-receptor antagonists have been performed predominantly in patients with an estimated creatinine clearance of 60ml/min or more. Here we determined renal hemodynamic effects of the V2-receptor antagonist Tolvaptan in 27 patients with ADPKD at various stages of chronic kidney disease: group A: >60, group B: 30–60, and group C: 2 . Measurements were performed before, after 3 weeks of Tolvaptan (up titration to 90/30mg/day, split dose), and 3 weeks after the last dose of Tolvaptan. With Tolvaptan, a minor, reversible decrease in GFR ( 125 I-iothalamate clearance) was found that reached significance in groups A and B: –7.8 (interquartile range –13.7 to –1.3) and –4.3 (–9.7 to –0.9) ml/min per 1.73m 2 , respectively, but not in group C (GFR decrease –0.7 (–1.1 to 1.5) ml/min/1.73m 2 ). The percentage change in GFR, ERPF ( 131 I-hippuran clearance), and filtration fraction with Tolvaptan did not differ between the three study groups. No differences between the three study groups were found in other main efficacy variables, besides smaller increases in urine volume in group C during Tolvaptan treatment. Tolvaptan was well tolerated, with only two patients withdrawing. Thus, doses of Tolvaptan typically used in patients with ADPKD do not produce a difference in renal hemodynamic profile in chronic kidney disease stages 1 through 4, but minor GFR drops may be observed in individual patients.
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Pharmacokinetic and Pharmacodynamic Interaction Between Tolvaptan and Warfarin in Healthy Subjects.
Clinical pharmacology in drug development, 2012Co-Authors: Susan E. Shoaf, Suresh MallikaarjunAbstract:Purpose: Tolvaptan, a nonpeptide V2 receptor antagonist approved in Japan and in the United States, is likely to be co-administered with warfarin in patients with heart failure (HF). Therefore, the effect of Tolvaptan on warfarin pharmacokinetics, pharmacodynamics, and protein binding was evaluated. Methods: An open-label, randomized, 2-period crossover trial was conducted involving healthy subjects (N = 24) administered 25 mg warfarin sodium on day 4 of a 13-day regimen of either 60 mg once daily Tolvaptan or matching placebo. Blood samples were taken over 240 hours postdose for analysis of Tolvaptan, R- and S-warfarin, and 7- and 10-hydroxywarfarin concentrations and for the measurement of activated partial thromboplastin time, prothrombin time, and international normalized ratio. Results: For S-warfarin, the geometric mean ratios (warfarin+Tolvaptan/warfarin alone; 90% confidence interval) for maximum plasma concentration (Cmax) and area under the concentration-time curve from time 0 to infinity (AUC∞) were 1.09 (1.05, 1.12) and 1.09 (1.04, 1.13), respectively. Corresponding ratios for R-warfarin were 1.06 (1.02, 1.09) and 1.05 (1.01, 1.11), respectively. No changes were observed in 7- or 10-hydroxywarfarin Cmax or AUC∞ values, prothrombin time, activated partial thromboplastin time, and international normalized ratio. The protein binding of racemic warfarin and Tolvaptan was not significantly altered by the presence of the other compound. Conclusion: Warfarin doses do not need to be altered when co-administered with Tolvaptan.
William J. Brock - One of the best experts on this subject based on the ideXlab platform.
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altered hepatobiliary disposition of Tolvaptan and selected Tolvaptan metabolites in a rodent model of polycystic kidney disease
Drug Metabolism and Disposition, 2019Co-Authors: James J Beaudoin, William J. Brock, Jacqueline Bezencon, Yanguang Cao, Katsuhiko Mizuno, Sharin E Roth, Kim L. R. BrouwerAbstract:Tolvaptan, a vasopressin V2-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 ± 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% ± 24.72% vs. 43.40% ± 18.11% in liver, 20.10% ± 9.15% vs. 21.17% ± 12.51% in outflow perfusate, and 0.08% ± 0.01% vs. 0.39% ± 0.32% in bile. DM-4103 recovery (mean ± S.D. percentage of dose) was decreased in PCK vs. WT bile (<0.01% ± <0.01% vs. 0.02% ± 0.01%; P = 0.0037), and DM-4107 recovery was increased in PCK vs. WT outflow perfusate (1.60% ± 0.57% vs. 0.43% ± 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.
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altered hepatobiliary disposition of Tolvaptan and selected Tolvaptan metabolites in a rodent model of polycystic kidney disease
Drug Metabolism and Disposition, 2019Co-Authors: James J Beaudoin, William J. Brock, Jacqueline Bezencon, Katsuhiko Mizuno, Sharin E Roth, Kim L. R. BrouwerAbstract:Tolvaptan, a vasopressin V2-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 ± 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% ± 24.72% vs. 43.40% ± 18.11% in liver, 20.10% ± 9.15% vs. 21.17% ± 12.51% in outflow perfusate, and 0.08% ± 0.01% vs. 0.39% ± 0.32% in bile. DM-4103 recovery (mean ± S.D. percentage of dose) was decreased in PCK vs. WT bile (
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candidate risk factors and mechanisms for Tolvaptan induced liver injury are identified using a collaborative cross approach
Toxicological Sciences, 2017Co-Authors: Merrie Mosedale, William J. Brock, Sharin E Roth, Yunjung Kim, Tim Wiltshire, Scott J Eaddy, Gregory R Keele, Robert W Corty, Yuying Xie, William ValdarAbstract:Clinical trials of Tolvaptan showed it to be a promising candidate for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) but also revealed potential for idiosyncratic drug-induced liver injury (DILI) in this patient population. To identify risk factors and mechanisms underlying Tolvaptan DILI, 8 mice in each of 45 strains of the genetically diverse Collaborative Cross (CC) mouse population were treated with a single oral dose of either Tolvaptan or vehicle. Significant elevations in plasma alanine aminotransferase (ALT) were observed in Tolvaptan-treated animals in 3 of the 45 strains. Genetic mapping coupled with transcriptomic analysis in the liver was used to identify several candidate susceptibility genes including epoxide hydrolase 2, interferon regulatory factor 3, and mitochondrial fission factor. Gene pathway analysis revealed that oxidative stress and immune response pathways were activated in response to Tolvaptan treatment across all strains, but genes involved in regulation of bile acid homeostasis were most associated with Tolvaptan-induced elevations in ALT. Secretory leukocyte peptidase inhibitor (Slpi) mRNA was also induced in the susceptible strains and was associated with increased plasma levels of Slpi protein, suggesting a potential serum marker for DILI susceptibility. In summary, Tolvaptan induced signs of oxidative stress, mitochondrial dysfunction, and innate immune response in all strains, but variation in bile acid homeostasis was most associated with susceptibility to the liver response. This CC study has indicated potential mechanisms underlying Tolvaptan DILI and biomarkers of susceptibility that may be useful in managing the risk of DILI in ADPKD patients.
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application of a mechanistic model to evaluate putative mechanisms of Tolvaptan drug induced liver injury and identify patient susceptibility factors
Toxicological Sciences, 2017Co-Authors: Jeffrey L Woodhead, William J. Brock, Kim L. R. Brouwer, Susan E. Shoaf, Sharin E Roth, Rachel J Church, Tom N Grammatopoulos, Linsey Stiles, Scott Q Siler, Brett A HowellAbstract:Tolvaptan is a selective vasopressin V2 receptor antagonist, approved in several countries for the treatment of hyponatremia and autosomal dominant polycystic kidney disease (ADPKD). No liver injury has been observed with Tolvaptan treatment in healthy subjects and in non-ADPKD indications, but ADPKD clinical trials showed evidence of drug-induced liver injury (DILI). Although all DILI events resolved, additional monitoring in Tolvaptan-treated ADPKD patients is required. In vitro assays identified alterations in bile acid disposition and inhibition of mitochondrial respiration as potential mechanisms underlying Tolvaptan hepatotoxicity. This report details the application of DILIsym software to determine whether these mechanisms could account for the liver safety profile of Tolvaptan observed in ADPKD clinical trials. DILIsym simulations included physiologically based pharmacokinetic estimates of hepatic exposure for Tolvaptan and2 metabolites, and their effects on hepatocyte bile acid transporters and mitochondrial respiration. The frequency of predicted alanine aminotransferase (ALT) elevations, following simulated 90/30 mg split daily dosing, was 7.9% compared with clinical observations of 4.4% in ADPKD trials. Toxicity was multifactorial as inhibition of bile acid transporters and mitochondrial respiration contributed to the simulated DILI. Furthermore, simulation analysis identified both pre-treatment risk factors and on-treatment biomarkers predictive of simulated DILI. The simulations demonstrated that in vivo hepatic exposure to Tolvaptan and the DM-4103 metabolite, combined with these 2 mechanisms of toxicity, were sufficient to account for the initiation of Tolvaptan-mediated DILI. Identification of putative risk-factors and potential novel biomarkers provided insight for the development of mechanism-based Tolvaptan risk-mitigation strategies.
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Hepatocellular Disposition and Transporter Interactions with Tolvaptan and Metabolites in Sandwich-Cultured Human Hepatocytes
Drug Metabolism and Disposition, 2016Co-Authors: Yang Lu, Jason R. Slizgi, Robert L. St. Claire, Kimberly M. Freeman, William J. Brock, Kenneth R Brouwer, Kim L. R. BrouwerAbstract:Tolvaptan is a selective V2-receptor antagonist primarily metabolized by CYP 3A. The present study investigated the hepatocellular disposition of Tolvaptan and the generated Tolvaptan metabolites, DM-4103 and DM-4107, as well as the potential for drug-drug interactions (DDIs) with metabolic and transport proteins in sandwich-cultured human hepatocytes (SCHH). Tolvaptan was incubated with SCHH and quantified by liquid chromatography–tandem mass spectrometry. Pioglitazone, verapamil, MK-571, and elacridar were used as inhibitors to investigate mechanisms of transport and metabolism of Tolvaptan and metabolites. Taurocholate (TCA), pravastatin, digoxin, and metformin were used as transporter probes to investigate which transport proteins were inhibited by Tolvaptan and metabolites. Cellular accumulation of Tolvaptan (0.15–50 μ M), DM-4103, and DM-4107 in SCHH was concentration-dependent. Tolvaptan accumulation (15 μ M) in SCHH was not altered markedly by 50 μ M pioglitazone, verapamil, MK-571, or 10 μ M elacridar. Coincubation of Tolvaptan with pioglitazone, verapamil, MK-571, and elacridar reduced DM-4107 accumulation by 45.6, 79.8, 94.5, and 23.0%, respectively, relative to control. Coincubation with increasing Tolvaptan concentrations (0.15–50 μ M) decreased TCA (2.5 μ M) cell+bile accumulation and the TCA biliary excretion index (BEI; from 76% to 51%), consistent with inhibition of the bile salt export pump (BSEP). Tolvaptan (15 μ M) had no effect on the cellular accumulation of 2.5 μ M pravastatin or metformin. Digoxin cellular accumulation increased, and the BEI of digoxin decreased from 23.9 to 8.1% in the presence of 15 μ M Tolvaptan, consistent with inhibition of P-glycoprotein. In summary, SCHH studies revealed potential metabolic- and transporter-mediated DDIs involving Tolvaptan and metabolites.
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multicenter study of long term safety of Tolvaptan in later stage autosomal dominant polycystic kidney disease
Clinical Journal of The American Society of Nephrology, 2021Co-Authors: Vicente E. Torres, Olivier Devuyst, Arlene B. Chapman, Ron T. Gansevoort, Ronald D. Perrone, Jennifer Lee, Molly Hoke, Alvin Estilo, Olga SergeyevaAbstract: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
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tolerability of aquaretic related symptoms following Tolvaptan for autosomal dominant polycystic kidney disease results from tempo 3 4
Kidney International Reports, 2017Co-Authors: Olivier Devuyst, Arlene B. Chapman, Frank S. Czerwiec, Susan E. Shoaf, Jaime D. BlaisAbstract:Introduction In the randomized placebo-controlled Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial, Tolvaptan slowed kidney growth and renal function decline in subjects with autosomal dominant polycystic kidney disease (ADPKD). Consistent with its primary pharmacologic activity, Tolvaptan use was commonly associated with aquaretic adverse events (AAEs) attributable to excess free water clearance. Methods A post hoc analysis of Tolvaptan-related discontinuations from the pivotal randomized controlled trial TEMPO 3:4 and its open-label extension TEMPO 4:4. Results In total, 750 of 961 Tolvaptan-treated subjects (78%) in TEMPO 3:4 reported at least one AAE. Of these 750 subjects, 72 (10%) discontinued because of an AAE (aquaretic-discontinued group) and 573 (76%) continued (aquaretic-continued group). The aquaretic-discontinued subjects were younger, had better baseline renal function, and had higher fasting urine osmolality than aquaretic-continued subjects. Of the 750 subjects reporting an AAE, 105 (14%) discontinued for another reason (non-aquaretic-discontinued group). Compared to non-aquaretic-discontinued subjects, aquaretic-discontinued subjects were more commonly male, had better baseline renal function, and discontinued the study drug faster. After 3 years of therapy, 75% of Tolvaptan subjects indicated that they could tolerate their current dose for the rest of their lives, compared to 85% of placebo subjects. These findings were corroborated by results in the open-label extension trial TEMPO 4:4. Discussion In this study, AAEs were common but well tolerated in ADPKD patients on Tolvaptan. ADPKD patients in earlier stages of disease progression may be more sensitive to aquaretic symptoms, which may help in guiding Tolvaptan dosing and titration decisions in the future.
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Urine Osmolality, Response to Tolvaptan, and Outcome in Autosomal Dominant Polycystic Kidney Disease: Results from the TEMPO 3:4 Trial
Journal of the American Society of Nephrology, 2016Co-Authors: Olivier Devuyst, Arlene B. Chapman, Ron T. Gansevoort, Eiji Higashihara, Ronald D. Perrone, Vicente E. Torres, Jaime D. Blais, Wen Zhou, John Ouyang, Frank S. CzerwiecAbstract:The vasopressin-cAMP-osmolality axis is abnormal in autosomal dominant polycystic kidney disease (ADPKD). In the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 Trial, a 3-year randomized, placebo-controlled trial in adults, the vasopressin V2 receptor antagonist Tolvaptan slowed ADPKD progression in patients with preserved GFR. Here, we investigated the determinants of baseline urine osmolality (Uosm) and its value as a severity marker of ADPKD, the factors influencing the response to Tolvaptan, and whether change in Uosm associated with key trial end points. At baseline, lower Uosm independently associated with female sex, presence of hypertension, lower eGFR, higher total kidney volume (TKV), and higher age. Tolvaptan consistently reduced Uosm by 200-300 mOsm/kg over 36 months. The Uosm response to Tolvaptan depended on baseline eGFR and Uosm. Subjects with greater change in Uosm experienced a significant reduction in clinical progression events. Among subjects receiving Tolvaptan, those with a greater suppression of Uosm had slower renal function decline. Assessment at follow-up, off medication, revealed a significant decrease in Uosm in both placebo and treated groups. Tolvaptan significantly increased plasma osmolality, which returned to baseline at follow-up. In conclusion, baseline Uosm in ADPKD reflects age, renal function, and TKV, and baseline Uosm, eGFR, and TKV influence the effect of Tolvaptan on Uosm. The greatest renal benefit occurred in subjects achieving greater suppression of Uosm, that is, those with better eGFR at baseline. These results support the link between vasopressin V2 receptor signaling and ADPKD progression.