Application of a mechanistic model to evaluate putative mechanisms of tolvaptan drug-induced liver injury and identify patient susceptibility factors

Jeffrey L. Woodhead, William J. Brock, Sharin E. Roth, Susan E. Shoaf, Kim L.R. Brouwer, Rachel Church, Tom N. Grammatopoulos, Linsey Stiles, Scott Q. Siler, Brett A. Howell, Merrie Mosedale, Paul B. Watkins, Lisl K.M. Shoda

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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 druginduced 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.

LanguageEnglish (US)
Pages61-74
Number of pages14
JournalToxicological Sciences
Volume155
Issue number1
DOIs
StatePublished - Jan 1 2017

Fingerprint

Chemical and Drug Induced Liver Injury
Liver
Autosomal Dominant Polycystic Kidney
Pharmaceutical Preparations
Wounds and Injuries
Respiration
Biomarkers
Metabolites
Toxicity
Clinical Trials
tolvaptan
Vasopressin Receptors
Polycystic Kidney Diseases
Pharmacokinetics
Hyponatremia
Therapeutics
Bile Acids and Salts
Alanine Transaminase
Hepatocytes
Assays

Keywords

  • ADPKD
  • DILI
  • DILIsym
  • Quantitative systems pharmacology modeling
  • Tolvaptan

ASJC Scopus subject areas

  • Toxicology

Cite this

Application of a mechanistic model to evaluate putative mechanisms of tolvaptan drug-induced liver injury and identify patient susceptibility factors. / Woodhead, Jeffrey L.; Brock, William J.; Roth, Sharin E.; Shoaf, Susan E.; Brouwer, Kim L.R.; Church, Rachel; Grammatopoulos, Tom N.; Stiles, Linsey; Siler, Scott Q.; Howell, Brett A.; Mosedale, Merrie; Watkins, Paul B.; Shoda, Lisl K.M.

In: Toxicological Sciences, Vol. 155, No. 1, 01.01.2017, p. 61-74.

Research output: Contribution to journalArticle

Woodhead, JL, Brock, WJ, Roth, SE, Shoaf, SE, Brouwer, KLR, Church, R, Grammatopoulos, TN, Stiles, L, Siler, SQ, Howell, BA, Mosedale, M, Watkins, PB & Shoda, LKM 2017, 'Application of a mechanistic model to evaluate putative mechanisms of tolvaptan drug-induced liver injury and identify patient susceptibility factors' Toxicological Sciences, vol. 155, no. 1, pp. 61-74. https://doi.org/10.1093/toxsci/kfw193
Woodhead, Jeffrey L. ; Brock, William J. ; Roth, Sharin E. ; Shoaf, Susan E. ; Brouwer, Kim L.R. ; Church, Rachel ; Grammatopoulos, Tom N. ; Stiles, Linsey ; Siler, Scott Q. ; Howell, Brett A. ; Mosedale, Merrie ; Watkins, Paul B. ; Shoda, Lisl K.M. / Application of a mechanistic model to evaluate putative mechanisms of tolvaptan drug-induced liver injury and identify patient susceptibility factors. In: Toxicological Sciences. 2017 ; Vol. 155, No. 1. pp. 61-74.
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