Drug Interactions between aprocitentan and obeticholic acid

GENERALLY AVOID: Coadministration with inhibitors of the bile salt efflux pump (BSEP) may increase accumulation of conjugated bile salts in the liver, including the glycine and taurine conjugates of obeticholic acid. Following daily administration of obeticholic acid, there was accumulation of the glycine and taurine conjugates, which have in vitro pharmacological activities similar to the parent drug. The metabolite-to-parent ratios of the glycine and taurine conjugates of obeticholic acid were 13.8 and 12.3 respectively, with chronic administration. In vitro data indicate that the taurine conjugate of obeticholic acid (tauro-obeticholic acid) is a substrate of BSEP. Consequently, concomitant use of medications that inhibit the BSEP, a canalicular membrane bile acid transporter, may result in further accumulation of tauro-obeticholic acid and other conjugated bile salts in the liver. Clinical symptoms and toxicities may occur. Additionally, obeticholic acid and its conjugates are selective and potent agonists for the farnesoid X receptor (FXR), the activation of which leads to induction of BSEP. Thus, inhibitors of BSEP may theoretically diminish the pharmacologic effects of obeticholic acid.

MANAGEMENT: Concomitant use of obeticholic acid with BSEP inhibitors should generally be avoided. If coadministration is required, serum transaminases and bilirubin should be closely monitored.