title: Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors.
abstract: 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.
authors.affiliation: DILIsym Services, Inc, Research Triangle Park, North Carolina.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Woodhead
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Brock Scientific Consulting, Montgomery Village, Rockville, Maryland.
authors.forename: William J
authors.initials: WJ
authors.lastname: Brock
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Rockville, Maryland.
authors.forename: Sharin E
authors.initials: SE
authors.lastname: Roth
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Rockville, Maryland.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Shoaf
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Kim L R
authors.initials: KL
authors.lastname: Brouwer
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|UNC Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina.
authors.forename: Rachel
authors.initials: R
authors.lastname: Church
authors.affiliation: BioEnergetics LLC, Boston, Massachusetts.
authors.forename: Tom N
authors.initials: TN
authors.lastname: Grammatopoulos
authors.affiliation: BioEnergetics LLC, Boston, Massachusetts.
authors.forename: Linsey
authors.initials: L
authors.lastname: Stiles
authors.affiliation: DILIsym Services, Inc, Research Triangle Park, North Carolina.
authors.forename: Scott Q
authors.initials: SQ
authors.lastname: Siler
authors.affiliation: DILIsym Services, Inc, Research Triangle Park, North Carolina.
authors.forename: Brett A
authors.initials: BA
authors.lastname: Howell
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|UNC Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina.
authors.forename: Merrie
authors.initials: M
authors.lastname: Mosedale
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.|UNC Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
authors.affiliation: DILIsym Services, Inc, Research Triangle Park, North Carolina; lshoda@dilisym.com.
authors.forename: Lisl K M
authors.initials: LK
authors.lastname: Shoda
mesh_terms: D065092:Antidiuretic Hormone Receptor Antagonists / Q000009:adverse effects* / Q000493:pharmacokinetics; D001552:Benzazepines / Q000493:pharmacokinetics / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D004198:Disease Susceptibility; D006801:Humans; D008954:Models, Biological; D000077602:Tolvaptan
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D000077602:Tolvaptan
keywords: ADPKD; DILI; DILIsym; quantitative systems pharmacology modeling.; tolvaptan