Ileal bile acid transporter inhibitors in Alagille syndrome and Progressive Familial Intrahepatic Cholestasis: A systematic review into dose-response.

Abstract

Ileal bile acid transporter inhibitors (IBATi), including maralixibat and odevixibat, are a novel approach to the treatment of paediatric cholestatic liver diseases, such as Alagille syndrome (ALGS) and different forms of progressive familial intrahepatic cholestasis (PFIC). Multiple phase 3 trials have demonstrated efficacy of IBATi in alleviating pruritus and decreasing serum bile acid (sBA) in a significant subset of patients. While most clinical IBATi trials included low-dose and high-dose treatment, a consistent dose-response effect has not been uniformly reported. This systematic review aims to assess the dose-response relationship for IBATi in patients with ALGS or PFIC, based on available pruritus, sBA and (non-)responder outcomes, identifying minimally effective dosage and exploring the potential for personalized dosing strategies. A systematic search was conducted across PubMed, EMBASE, Web of Science and Cochrane Library of articles, oral presentations, posters presentations and abstracts up to 29 July 2024. The analysis included 75 records, of which 68 reported sBA and 63 reported pruritus outcomes. An evident dose-response relationship was not observed for either maralixibat or odevixibat in PFIC or ALGS. In the case of odevixibat, outcomes measures for patients with ALGS have only been reported for a dosage of 120 μg/kg/day. In conclusion, the variability in therapeutic outcomes of different doses for all IBATi underscores the necessity for personalization of dosing, which may include decreasing the dosage for responders to IBATi.