The pharmacokinetics of infliximab induction therapy in patients with moderate to severe ulcerative colitis

Abstract

Background: The mechanism behind primary non-response to infliximab (IFX) in patients with Ulcerative Colitis (UC) is not fully understood. Although insufficient serum concentrations of IFX have been suggested as a cause of lack of response associated with a high inflammatory load (and hence large quantities of TNF to be neutralized), the early pharmacokinetics (PK) of IFX during induction therapy have been poorly studied. We studied the PK of IFX induction treatment related to inflammatory load and response in patients with moderate and severe UC. Methods: In this multicenter prospective observational study anti- TNF Naive patients with moderate-to-severe Ulcerative Colitis (Endoscopic Mayo 2/3) starting on IFX were included after baseline endoscopy. Serum IFX concentrations, antibodies to IFX and fecal samples (IFX concentration) were collected at 10 serial time points during the first 6 weeks of induction therapy. Response was defined by endoscopic improvement at week 6-8. PK was analysed by nonlinear mixed-effects modelling and described using a 2-compartiment PK model. Results: Fifteen UC patients were included. All but one patient received IFX according to the regular induction regime of 5mg/kg at week 0,2,6 and 7/15 with concomitant thiopurines. 8/15 patients had no endoscopic improvement. Typical values and corresponding inter-patient variability (IPV) for clearance, intercompartimental clearance, central and peripheral volume of distribution were 0.44 L/day (IPV 26%), 0.52 L/day, 3.5 L (IPV 20%) and 3.2 L (IPV 130%). Median 'trough' level before third infusion (week 6) was 2.5 ug/ml for endoscopic non-responders versus 8.2 ug/ml for responders (P=0.03). Serum IFX of <7ug/ml at day 42 was defined as a cut-off with OR:36 (95%CI 1.8-719, P= 0.03) to predict endoscopic non-response. Four patients (1/4 used concomitant thiopurine) developed antibodies to IFX at week 6, clearance was 4.4 fold increased and peripheral volume of distribution was 0.05 fold decreased in these patients. Fecal IFX at day 1 was significantly higher (P=0.02) for non-responders compared to responders. Average (+/- SD) post-hoc area under the IFX concentration versus time curve (AUC) was 1204 +/- 507 mg/ L/day 49 in the non-responders compared to 1417 +/- 444 mg/L/day for the responders (p= 0.42). Conclusions: A wide variation in early serum concentrations of infliximab was observed. Primary non-responders have lower serum concentrations at induction compared to responders, as well as increased fecal concentrations in the first days of treatment and in some instances early development of antibodies to infliximab. (Figure Presented).