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.

The DILI‐sim Initiative: Insights into Hepatotoxicity Mechanisms and Biomarker Interpretation

“…However, DILIsym modeling has shown with certain drugs and metabolites with BSEP IC 50 values > 25 μM, bile acid accumulation can still contribute significantly to toxicity if one or both of the other mechanisms are operative. This was the case with modeling tolvaptan hepatotoxicity …”

“…The success of DILIsym in predicting hepatotoxicity by integrating drug effects on multiple bile acid transporters is the strongest support for the role of bile acid accumulation as a cause of human hepatotoxicity. 13,16,21,22 Importantly, the modeling has identified key data gaps to help prioritize research in the field. 23 Another issue brought to light by the modeling was the importance of the mechanism whereby a drug inhibits BSEP.…”

“…This was the case with modeling tolvaptan hepatotoxicity. 22 Identification of mechanisms underlying species differences in susceptibility to DILI It has long been appreciated that species differences in metabolism may underlie differences in susceptibility to hepatotoxicity. DILIsym modeling has also provided additional explanations for species differences in susceptibility on the basis of the three mechanisms.…”

“…25 Mechanisms underlying idiosyncratic DILI It is increasingly appreciated that delayed, idiosyncratic hepatotoxicity is frequently the result of an adaptive immune attack on the liver. 26 However, it is important to note that DILIsym successfully predicted the liver safety liability of three drugs that cause delayed idiosyncratic DILI, troglitazone, 13 tolvaptan, 22 and TAK-875. 16 This supports the generally accepted concept that drug-induced hepatocyte stress is necessary to stimulate an adaptive immune attack on the liver 26 and that this stress may be generally caused by the three mechanisms assayed in DILIsym.…”

Tolvaptan in the treatment of autosomal dominant polycystic kidney disease: patient selection and special considerations

“…Only half of the patients rechallenged with tolvaptan experienced ALT reelevation. 30 The EMA has estimated that the number of patients currently exposed is insufficient to exclude rare but severe liver toxicity and that tolvaptan could potentially cause severe hepatitis in 1 in 4,000 patients. A risk management plan (included in the summary of product characteristics) has, therefore, been specifically set up.…”