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P637 Anti-infliximab antibody concentrations guide therapeutic decision-making in patients with Crohn's disease losing clinical response

Dreesen E.*1, Van Stappen T.1, Ballet V.2, Tops S.1, Compernolle G.1, Van Assche G.2, Ferrante M.2, Vermeire S.2, Gils A.1

1KU Leuven, P.O. Box 820 Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium 2UZ Leuven, Campus Gasthuisberg, Department of Gastroenterology and Hepatology, Leuven, Belgium

Background

Loss of clinical response (LOR) to infliximab (IFX) maintenance therapy in patients with Crohn's disease (CD) may necessitate treatment intensification. We explored the pharmacokinetics and effectiveness of infusion interval shortening (IS) and dose doubling (DD) and whether IFX and antidrug antibody (ADA) trough concentrations (TC) can guide therapeutic decision-making.

Methods

A retrospective cohort study was conducted, including 93 patients with CD who received a double dose IFX (10 mg/kg body weight) and/or a next infusion after a shortened interval following LOR during maintenance therapy. IFX TC and ADA were measured at consecutive time points just before (at T0) and after (at T+1) the treatment intensification. ADA were quantified using an in-house developed drug tolerant assay (1). We compared the short-term evolution of IFX exposure, immunogenicity, clinical (based on physician global assessment) and biological (based on CRP) response during DD, IS and combined DD+IS.

Results

Overall, treatment intensification significantly increased the IFX TC from 1.2 μg/mL to 3.6 μg/mL (93 paired samples, p<0.0001) (Table 1). An ADA concentration below 481 ng/mL eq. predicted a therapeutic post-treatment TC (3 μg/mL, 100% specificity, 51% sensitivity, AUROC 0.83, p<0.0001). When ADA were undetectable, all treatment intensification interventions significantly increased the IFX TC and DD+IS resulted in a larger TC increase compared to DD alone (Table 1). When ADA were detectable but below the 481 ng/mL eq. cut-off, only DD significantly increased the IFX TC. When ADA were above the 481 ng/mL eq. cut-off, neither treatment intensification intervention was effective for increasing the IFX TC.

A significant TC increase was associated with clinical response in patients undergoing IS, only when they had no detectable ADA (from 2.3 μg/mL [0.7–4.4] to 4.9 μg/mL [1.7–12.1], n=15, p=0.009). Even when ADA were detectable but below the 481 ng/mL eq. cut-off, a significant TC increase was associated with clinical and biological response and remission in patients undergoing DD (biological response: from 1.5 μg/mL [0.4–3.1] to 6.0 μg/mL [3.3–13.5], n=8, p=0.02; biological remission: from 1.7 μg/mL [0.3–3.4] to 4.0 μg/mL [3.2–13.7], n=7, p=0.03; clinical response: from 2.0 μg/mL [1.0–6.2] to 9.2 μg/mL [4.4–13.5], n=8, p=0.008).

Table 1. Course of the IFX pharmacokinetics during treatment intensification

TotalISDDDD+IS
T0T+1T0T+1T0T+1T0T+1
IFX TC1.2 [0.3–3.6]3.6 [0.5–10.2]0.8 [0.3–3.4]1.7 [0.3–5.5]2.0 [0.3–4.7]4.0 [1.0–10.9]1.2 [0.3–1.7]6.1 [4.7–11.1]
(n=93)(n=93)(n=35)(n=35)(n=45)(n=45)(n=13)(n=13)
p<0.0001p<0.0001p<0.0001p=0.0005
IFX TC when ADA are undetectable2.4 [1.1–5.4]7.4 [3.0–12.6]3.1 [0.7–5.7]5.4 [1.9–15.6]3.4 [1.3–6.0]5.5 [2.9–11.8]1.7 [1.2–2.2]10.7 [8.3–13.7]
(n=49)(n=49)(n=17)(n=17)(n=25)(n=25)(n=7)(n=7)
p<0.0001p=0.0002p<0.0001p=0.02
IFX TC when ADA are low0.8 [0.3–1.8]3.8 [1.0–8.6]0.7 [0.4–1.1]1.2 [0.4–2.3]1.5 [0.4–3.7]7.2 [3.3–13.5]0.3 [0.3–0.7]5.2 [2.8–5.9]
(n=26)(n=26)(n=9)(n=9)(n=12)(n=12)(n=5)(n=5)
p<0.0001p=0.1p=0.002p=0.06
IFX TC when ADA are high0.3 [0.3–0.3]0.3 [0.3–0.3]0.3 [0.3–0.3]0.3 [0.3–0.4]0.3 [0.3–0.3]0.3 [0.3–0.3]0.3 [0.3–0.3]0.3 [0.3–0.3]
(n=17)(n=17)(n=8)(n=8)(n=8)(n=8)(n=1)(n=1)
p=0.6p=0.3p=1.0

All values are median [IQR], g/mL.

Conclusion

DD is more effective than IS for restoring therapeutic TC and clinical and biological response and remission in patients with low ADA titers. When ADA titers are high, neither treatment intensification strategy is effective.