Pretreatment serum bile acid composition and predictability of subsequent response to odevixibat in patients with bile salt export pump (BSEP) deficiency

Background & Aims: Bile salt export pump (BSEP) deficiency, or progressive familial intrahepatic cholestasis type 2, is a genetic liver disease characterized by defective biliary bile acid secretion. Odevixibat, an ileal bile acid transporter inhibitor (IBATi), impairs intestinal reabsorption of conjugated bile acids, reducing serum bile acid (sBA) concentration in some patients with BSEP deficiency. We evaluated association of pretreatment sBA levels and composition, and subsequent response to odevixibat in patients with BSEP deficiency to improve our understanding of the mechanism. Approach & Results: In this blinded post hoc analysis, pretreatment sBAs from 41 odevixibat-treated patients with BSEP deficiency who participated in PEDFIC were analyzed using liquid chromatography-tandem mass spectrometry. Patients were divided into sBA responders (Rs) and non-responders (NRs). Association of pretreatment individual sBAs with subsequent response was evaluated and receiver operating characteristic (ROC) curves were constructed to identify discriminating cutoff values. Rs had higher pretreatment percentages of unconjugated cholic acid (CA; area under the ROC curve [AUC]: 0.70 [95% CI: 0.52–0.87; P=0.03]), unconjugated chenodeoxycholic acid (CDCA; AUC: 0.73 [0.56–0.90]; P=0.01), and concentration of CA + CDCA (AUC: 0.76 [0.61–0.92]; P=0.001). When ≥1 of 3 cutoffs were reached, 36/41 (87.8%) patients with BSEP deficiency were correctly classified as subsequent Rs (17/19; sensitivity: 89.5%) or NRs (19/22; specificity: 86.4%). Conclusions: Higher pretreatment serum levels of unconjugated CA and CDCA are associated with subsequent response to odevixibat in patients with BSEP deficiency. Response to odevixibat may be related to residual biliary bile acid secretion capacity in patients with BSEP deficiency.