Optimizing the switch from escalated intravenous to subcutaneous infliximab: a population pharmacokinetics–pharmacodynamics study

It remains unclear if patients on escalated intravenous (IV) infliximab can switch to standard subcutaneous (SC) infliximab CT-P13 of 120 mg bi-weekly (Q2W) injections without losing therapeutic response. This study investigates the dose-exposure-response relationship during the IV-to-SC switching of infliximab in Crohn's disease (CD) and ulcerative colitis (UC). Data were collected from healthy volunteers and patients with CD and UC in different Phase I studies. In patients, PK, fecal calprotectin (FC), and endoscopic remission (ER) in CD or endoscopic improvement (EI) in UC were measured during switching from 5 mg/kg IV infliximab to Q2W SC infliximab injections of 120/180/240 mg. We performed population pharmacokinetics-pharmacodynamics modeling and simulation (n = 1,000 virtual patients) to evaluate FC time courses and probabilities of ER/EI post-switch. FC levels decreased when overall infliximab exposure (not just infliximab trough concentrations) increased. Lower FC at week (w)14 was associated with increased probabilities of EI in UC, but not ER in CD. Simulations showed that the standard infliximab IV-to-SC switch at w6 further decreases FC and results in a higher probability of EI at w22/30 (54% if no switch vs 63% if switch). Virtual patients on escalated Q6W/Q8W IV maintenance regimens up to 10 mg/kg can switch to 120 mg Q2W SC infliximab without FC increases. In addition, we translated our model into a clinical software tool to guide the IV-to-SC switch of infliximab. Patients on Q6W and Q8W IV regimens may switch to standard SC infliximab without an increase in FC.