P462 Upfront infliximab dose intensification for secondary loss of response in IBD: similar efficacy to dose interval shortening with the added advantage of early clinical and pharmacokinetic predictors of response
Srinivasan, A.(1,2,3);De Cruz, P.(3,4);Sam, M.(5,6,7);Toong, C.(5,6,7,8);van Langenberg, D.(1,2);
(1)Eastern Health, Department of Gastroenterology, Melbourne, Australia;(2)Monash University, Eastern Health Clinical School, Melbourne, Australia;(3)Austin Health, Department of Gastroenterology, Melbourne, Australia;(4)University of Melbourne, Austin Academic Centre, Melbourne, Australia;(5)NSW Health Pathology Liverpool Hospital, Department of Immunopathology, Sydney, Australia;(6)Ingham Institute of Applied Sciences, Immunology Research Group, Sydney, Australia;(7)University of NSW, South Western Sydney Clinical School, Sydney, Australia;(8)Liverpool Hospital, Department of Immunology, Sydney, Australia;
The efficacy and pharmacokinetic profile of upfront dose intensification strategies such as re-induction (RI) have not been well described, nor directly compared with more prevalent intensification strategies to address secondary loss of response (LOR) in inflammatory bowel disease (IBD). Hence this study aimed to prospectively compare infliximab RI and 6-weekly dose interval shortening (DIS) with reference to clinical and pharmacokinetic effectiveness, and to identify early predictors of response.
A prospective multicentre parallel cohort study of consecutive patients with IBD who underwent dose intensification to address secondary LOR using (1) infliximab RI (i.e. repeat week 0,2,6 dosing) followed by 8-weekly maintenance, or (2) 6-weekly DIS, over 30 weeks (6 doses) was undertaken. Primary outcomes were: (1) Clinical response, defined as a decrease in Harvey Bradshaw Index ≥3 or partial Mayo score ≥2 from pre-intensification baseline, assessed at weeks 12 and 32, and (2) Clinical and pharmacokinetic predictors of week 32 response, with serum infliximab samples collected at predefined timepoints (Figure 1). Patients who were dose intensified in the absence of clinical symptoms, were excluded from the primary analysis.
Of 104 patients, 54 underwent RI and 50 underwent 6-weekly DIS (Table 1), including 43 patients from each cohort who were dose intensified to address clinically active disease. Baseline infliximab trough levels prior to RI and DIS (2.03 v 2.02ug/ml, p=0.83) were comparable. Clinical response was similar across both RI and DIS cohorts at weeks 12 (70 v 65%, p=0.89) and 32 (53 v 63%, p=0.51). Multivariate logistic analyses demonstrated that objectively verified active disease at baseline (OR 20.43[2.53-64.94]; p=0.005) and clinical response at week 12 (OR 15.44[1.20-19.97]; p=0.036) were associated with week 32 response, as were week 2 infliximab levels within the RI cohort only (OR 1.34[1.02-1.47]; p=0.036). Following RI, week 2 infliximab levels below 15.6ug/ml (sensitivity 100.0%; specificity 42.9%; AUROC 0.76; p<0.05) were predictive of not achieving clinical response at week 32; potentially indicating that amongst this patient subset, week 12 clinical response may be useful in differentiating between early clinical responders who may benefit from sequential DIS following RI to prevent subsequent non-response, and early clinical non-responders who may benefit from early biologic switching.
Despite similar clinical outcomes across both dose intensification strategies, only upfront dose intensification using infliximab RI was associated with early clinical and pharmacokinetic predictors of response capable of facilitating early dose optimisation and biologic switching.