Abstract
Pruritus is a common complication of cholestatic liver diseases. Inhibition of the ileal bile acid transporter (IBAT/ASBT) may emerge as treatment option. Our aim was to assess tolerability and effect on pruritus of the selective IBAT inhibitor A4250 in patients with primary biliary cholangitis (PBC). Ten patients with PBC and bile acid sequestrant treatment of cholestatic pruritus were after a two-week wash out of the bile acid sequestrant treated with either 0.75 mg (n = 4) or 1.5 mg (n = 5) of A4250 for four weeks. Patients’ pruritus was assessed by Visual Analogue Scale (VAS), 5-D itch scale and the pruritus module of the PBC40 questionnaire. Plasma bile acids and 7α-hydroxy-4-cholesten-3-one were measured by UPLC-MS/MS, plasma fibroblast growth factor 19 by ELISA, and serum autotaxin activity by homemade assay. All nine patients exposed to A4250 reported a remarkable improvement in pruritus, until none or mild according to 5-D itch, VAS and PBC40 pruritus. Five patients finished the study prematurely due to abdominal pain (5/5) and diarrhoea (4/5). The high incidence of probably bile acid malabsorption-related diarrhoea and abdominal pain in the bile acid sequestrant pre-treated population indicates that the start dose of A4250 may have been too high for adult patients.
Highlights
Primary Biliary Cholangitis (PBC) is a chronic immune-mediated liver disease characterized by progressive cholestasis, biliary fibrosis and eventually cirrhosis[1]
We have recently shown in a phase I trial that oral administration of A4250 in healthy volunteers induced substantial effects on bile acid synthesis and plasma and faecal bile acids, which likely results from the decreased ileal FXR-dependent FGF19 secretion
Patients with primary biliary cholangitis (PBC) fulfilling inclusion criteria were screened from local data bases at Sahlgrenska and Karolinska University Hospitals consisting of about 500 patients of which slightly more than 10% had been prescribed a bile acid sequestrant for cholestatic pruritus
Summary
Primary Biliary Cholangitis (PBC) is a chronic immune-mediated liver disease characterized by progressive cholestasis, biliary fibrosis and eventually cirrhosis[1]. Second-line treatment of PBC with obeticholic acid may even deteriorate pruritus[5] Bile acid sequestrants such as cholestyramine and colestipol are often administered to treat pruritus, but their effectiveness in practice is limited. Since all available treatment options for cholestatic pruritus lack long-term efficacy and have side effects[9] liver transplantation may be indicated even without advanced liver failure. For those reasons, there is a high need to find an effective and safe antipruritic treatment for patients with PBC and other cholestatic liver diseases that are complicated by pruritus. The aim of our current pilot study was to assess safety and tolerability, and potential improvements of pruritus of oral A4250 in patients with PBC and bile acid sequestrant pre-treated cholestatic pruritus
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