Analysis of C4 Concentrations to Predict Impact of Patient-Reported Diarrhea Associated With the Ileal Bile Acid Transporter Inhibitor Linerixibat.

Linerixibat, an ileal bile acid transporter (IBAT) inhibitor, is being evaluated for the treatment of pruritus in primary biliary cholangitis (PBC). Diarrhea is commonly reported with this drug class as IBAT inhibition redirects bile acids (BA) to the colon. Serum 7-alpha-hydroxy-4-cholesten-3-one (C4) measurement is a validated method to identify BA diarrhea. To inform dose selection, we characterized the relationship between linerixibat dose, C4 levels, and patient-reported bother on the gastrointestinal symptom rating scale (GSRS) diarrhea question. A kinetic-pharmacodynamic model was developed using data from five Phase 1/2 trials, to describe the effect of linerixibat dose (1-180 mg) and regimen (once/twice daily) on C4 concentrations over time. GSRS data from patients with PBC and pruritus in the Phase 2b GLIMMER study (NCT02966834) were used to develop a proportional odds model to predict the probability of a score of 1-7 (no-very severe discomfort) to the question "Have you been bothered by diarrhea during the past week?" in relation to linerixibat dose. The two models were linked to describe the linerixibat dose-C4-diarrhea bother relationship. Models were validated using graphical and numerical assessment and visual predictive checks. Linerixibat caused dose-dependent increases in C4 until saturation (~180 mg total daily dose). Increased C4 concentrations trended with increased GSRS diarrhea scores. Simulations demonstrated increases in moderate-to-very severe (≥ 4) diarrhea scores with increasing linerixibat dose. Increases in patient-reported diarrhea scores were linerixibat dose-dependent. Selecting an optimal dose that maximizes linerixibat's ability to improve pruritus while minimizing patient-reported diarrhea bother is important to support treatment adherence.