DILIsym modeling predicted that lixivaptan would have substantially improved liver safety over tolvaptan in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) (View publication here).  It was recently announced that the ALERT study of ADPKD patients was terminated when one of the lixivaptan-treated patients experienced elevations in serum ALT to 6 X ULN and alternate causes were not evident (View press release here.)  It is important to note that this study only enrolled ADPKD patients who had terminated treatment with tolvaptan due to liver toxicity.  In addition, it has not been publicly stated how many of the patients in the ALERT trial were able to be safely treated with lixivaptan.  Therefore, DILIsym prediction that the lixivaptan is safer for the liver than tolvaptan has not been tested.   It should also be noted that DILIsym only predicts the initial liver events that likely culminate in a T-cell-mediated attack on the liver.   Patients who have experienced tolvaptan liver toxicity may have memory t-cells that, given the structural similarity of tolvaptan and lixivaptan, could result in a much lower threshold to stimulate a liver directed attack.

Dr. Paul B. Watkins

Director, Institute for Drug Safety Sciences

Howard Q. Ferguson Distinguished Professor of Pharmacy

DILIsym Scientific Advisory Board Member

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