P317 Ustekinumab Trough Concentrations Associated with Biochemical Outcomes in Patients with Crohn’s Disease

Abstract

Abstract Background Ustekinumab (UST) is a monoclonal antibody which binds to the p40 subunit of interleukins-12/23 and is an effective and safe treatment for patients with Crohn’s disease (CD). An association between serum drug concentrations and therapeutic outcomes is required to justify Therapeutic Drug Monitoring (TDM). However, it is currently unknown if TDM is of additional value in UST treatment. We assessed the exposure-biochemical response relationship of UST trough concentrations at week, 8 in a prospective, real-world setting. Methods We performed a prospective study in CD patients with biochemical, radiologic or endoscopic disease activity in four academic centers in the Netherlands. All patients (n=90) received weight adjusted intravenously (IV) UST induction. First subcutaneous (SC), 90 mg induction dose was administered at week, 8 followed by a maintenance dose of, 90 mg SC every, 8 or, 12 weeks, at the discretion of the physician. Blood for drug levels were drawn at different time points during follow up (median follow up was, 52 weeks (IQR, 50–52)) with a median amount of, 2 measurements (IQR, 1–4) per patient. Plasma concentrations of UST were determined by means of a validated enzyme-linked immune assay. A population pharmacokinetic (PK) model was developed based on these measurements and the UST FDA review documents. Subsequently, the individual UST concentration time course during treatment were predicted using the developed model. Corticosteroid-free clinical remission (HBI ≤, 4) and biochemical remission (C-reactive protein (CRP) ≤5 mg/L or faecal calprotectin (FC) ≤, 250) were assessed at week, 12 and, 24. Quartile analysis and logistic regression was performed to analyse if UST concentration at week, 8 was associated with biochemical remission rates at week, 24. An independent cohort of, 34 patients was used to validate the primary outcomes. Results Basis characteristics of all patients are shown in table 1. Median estimated trough concentrations of UST were, 4.23 µg/mL (IQR, 2.79–5.83) and, 7.19 µg/mL (IQR, 3.30–10.67) at week, 8 in the primary and validation cohort respectively. Patients achieving biochemical remission at week, 12 and, 24 had statistically significantly higher UST levels at week, 8 (P<0.01) compared to patients without biochemical remission (fig, 1). Also, higher UST levels at week, 8 were associated with better biochemical remission rates at week, 12 and, 24 in quartile analysis and logistic regression (fig, 2,3). Associations of UST levels at week, 8 and biochemical remission at week, 12 and, 24 were confirmed in the validation cohort. No UST antibodies were detected. Conclusion In this real-world cohort of CD patients, ustekinumab levels of ≥5.9 µg/mL at week, 8 were associated with higher biochemical remission rates at week, 12 and, 24.