Dose intensification strategy influences infliximab pharmacokinetics but not clinical response after the same number of doses.

Abstract

The optimal infliximab dose intensification strategy to address secondary loss of response (LOR) remains unclear. This study aimed to compare clinical and pharmacokinetic outcomes following (i) upfront infliximab re-induction with (ii) ongoing 6-weekly dose interval shortening (DIS), after the same number of doses. A prospective parallel cohort study of inflammatory bowel disease patients who required infliximab dose intensification for secondary LOR using (i) re-induction (i.e., repeat 5mg/kg 0, 2, 6-week dosing) followed by 8-weekly maintenance or (ii) 6-weekly 5mg/kg DIS was undertaken. Week 32 clinical response was the primary outcome, with secondary evaluation of infliximab pharmacokinetics and predictors of response. Of 104 patients, 54 underwent re-induction, and 50 underwent 6-weekly DIS; 43 per cohort had clinically active disease, with comparable baseline infliximab levels (2.03 vs 2.02ug/mL, P=0.83). Clinical response was similar across re-induction and DIS cohorts at weeks 12 (69.8 vs 65.1%) and 32 (53.5 vs 62.8%, each P>0.50); however, both strategies demonstrated distinct pharmacokinetic profiles at weeks 6 (18.45 vs 5.36ug/mL, P<0.01), 12 (8.94 vs 5.96ug/mL, P=0.02) and 30 (3.89 vs 6.35ug/mL, P=.0.02). In multivariable analyses, objectively verified active disease at baseline (OR 12.92, 95% CI [1.84-90.84], P=0.01), subtherapeutic week 6 infliximab levels (OR 0.12, 95% CI [0.01, 0.99], P=0.049) and week 12 clinical response (OR 5.44, 95% CI [1.20-19.97], P=0.04) were associated with week 32 response, as were week 2 infliximab levels (OR 1.34, 95% CI [1.02-1.47], P=0.04) following re-induction. Following re-induction, week 2 infliximab levels <15.6ug/mL (AUROC 0.76, 95% CI [0.54-0.99], P<0.05) predicted nonresponse at week 32. Dose intensification strategy impacted immediate and sustained infliximab levels but not clinical response. Upfront intensification was associated with short-term pharmacokinetic advantages, including predictors of response, that diminished with time. Hence, when applying upfront dose intensification, clinicians should consider continuing intensified dosing to sustain early pharmacokinetic advantages based on predictors of (non)response.