S725 linical Utility of Precision-Guided Dosing Tool for Infliximab During Maintenance Therapy of Inflammatory Bowel Disease

Abstract

Introduction: A precision-guided dosing tool that uses Bayesian data assimilation was developed to forecast Infliximab (IFX) exposure. Our objective was to establish the utility of the tool in clinical decision making during IFX maintenance therapy when used reactively, to address inadequate disease control that results from suboptimal exposure, and proactively, to sustain exposure commensurate with disease remission in inflammatory bowel disease (IBD). Methods: Blood specimens were collected, anytime beyond 20 days after a prior infusion in a prospective study (EMPOWER). Pharmacokinetic (PK) testing was conducted at Prometheus Laboratories (San Diego, CA). Serum IFX, antibodies to IFX (ATI) and albumin concentrations were all imputed with dosing regimen and weight in a Bayesian data assimilation tool to produce individualized PK profiles that forecasted IFX concentration and time to trough concentration below pre-specified thresholds (e.g., < 10 µg/mL). Forecasted exposure at various dosing regimens was also provided. Physician’s global assessment of disease activity was collected with the decision to change IFX dosing that resulted from PK test results. Statistical analysis consisted of Mann-Whitney and Fisher Exact test as appropriate. Results: A total of 111 patients were assessed by 21 physicians. A change in IFX dose regimen was initiated in 51 patients (46%). Inadequate exposure and forecasted IFX levels below 10 µg/mL associated with dose intensification (76%, median IFX 6.3 µg/mL) (p< 0.01), with lower remission rate (23.5%) achieved in that group as compared to two other groups having better disease control and PK profiles (p< 0.001) (Table). Forecasted IFX levels below 10 µg/mL were associated with 4-fold higher likelihood of active disease (OR=4.1; 95%CI: 1.7-9.4) as compared to IFX levels above 10 µg/mL (p< 0.01). Time to trough below 10µg/mL was shorter in active disease (median: 46 days, IQR: 32-59) than in remission (median 57 days, IQR: 48-69) (p< 0.001). As presented in Figure, dose intensification using a 5 mg/kg every 4 weeks dosing regimen forecasted 2.3-fold higher IFX levels as compared to a 10 mg/kg every 8 weeks dosing regimen (median of 17.1 vs 7.4 µg/mL, respectively) (p< 0.001). Similar results were observed among patients presenting with disease remission. Conclusion: Our study suggests that the precision-guided dosing tool provides clinical utility and helps with dose adjustments in both interval changes as well as dose intensification.Figure 1.: Forecasted IFX Exposure at various dose and interdose intervals, given the individual PK parameters Table 1. - Patient Characteristics (n=111), by treatment intervention based on test results Variable IFX Dose RegimenReductionN=17 IFX Dose RegimenContinuationN=60 IFX Dose RegimenIntensificationN=34 OverallPopulationN=111 Patient Characteristics Age (years) 16 (14-19) 32 (18-45) 32 (17-46) 26 (16-44) Female (%, n/N) 44.1% (7/17) 43.3% (26/60) 44.1% (15/34) 43.2% (48/111) CD/UC/Indeterminate 13/3/1 36/15/8 22/9/3 71/27/12 Weight (Kg) 64 (43-76) 71 (61-92) 69 (61-92) 70 (60-84) Dose mg/Kg 10.0 (9.0-10.4) 8.2 (5.0-10.0) 5.5 (5.0-10.0) 8.0 (5.1-10.0) Interdose interval (weeks) 6 (5-8) 8 (6-8) 8 (6-8) 8 (6-8) PGA Remission Status, remission (%, n/N) 70.6% (12/17) 41.7% (25/60) 23.5% (8/34) 40.5% (45/111) Clinical PK Measurements Measured IFX levels (µg/mL) 23.3 (17.2-28.5) 12.9 (7.2-20.6) 8.0 (5.2-14.7) 12.5 (7.2-20.9) ATI status (%, n/N) 0% (0/17) 10.0% (6/60) 11.8% (4/34) 9.0% (10/111) Albumin (g/dL) 4.1 (4.0-4.3) 4.0 (3.6-4.2) 3.9 (3.7-4.2) 4.0 (3.7-4.2) Clearance (L/day) 0.19 (0.15-0.22) 0.27 (0.20-0.33) 0.28 (0.22-0.35) 0.25 (0.19-0.31) Time to Trough < 10 µg/mL (weeks) 11 (10-12) 7 (6-9) 6 (4-7) 7 (6-9) Forecasted Trough (µg/mL) 26.2 (20.1-34.5) 12.7 (8.6-17.6) 6.3 (3.1-9.4) 11.6 (6.5-19.5) Forecasted Trough < 10 µg/mL 0% (0/17) 31.7% (19/60) 76.5% (26/34) 40.5% (45/111)