Tag Archives: subcutaneous infliximab

Infliximab Thresholds with Subcutaneous vs Intravenous Administration for Crohn’s Disease

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SN Hong et al. AP&T 2024; 0:1–10. doi.org/10.1111/apt.18354. Subcutaneous Infliximab Concentration Thresholds for Mucosal and Transmural Healing in Patients With Crohn’s Disease

Background: The exposure–response relationship for the intravenous (IV) formulation of infliximab is well established, with multiple studies demonstrating that higher trough concentrations (C-trough) are associated with improved patient outcomes…However, the 2-week cycle of subcutaneous administration showed many-fold higher C-trough than the 8-week cycle of IV-IFX. Direct comparison of C-trough between SC- and IV-IFX is not appropriate because of different bioavailability and concentration–time profile. It is also not appropriate to apply the C-trough thresholds that predict achieving the therapeutic targets for IV.

This was a cross-sectional retrospective study with 124 patients with Crohn’s disease (CD) who had received SC-IFX maintenance therapy for ≥6 months. SC-IFX C-trough was measured immediately before SC-IFX injection. Key findings:

  • Mucosal healing (MH) was noted in 77.9% (74/95) and transmural healing (TH) in 36.3% (37/102).
  • SC-IFX C-trough was significantly higher in patients with MH (24.1 vs.16.9 μg/mL; p=0.001) and TH (26.0 vs. 20.5 μg/mL; p=0.007) than in those without.

Discussion:

Target trough levels: In this study, the authors found that “the C-trough thresholds for clinical remission, biochemical remission, MH and TH were 12, 16, 18 and 30 μg/mL, respectively, based on ROC analysis. The C-trough of SC-IFX increased with the depth of remission.”

Why trough level targets may differ between IV administration and SC: Administration via the IV route results in early and rapid peak concentration followed by a steady decline to trough, whereas administration via the SC route has slower absorption, lower bioavailability, lower peak concentration and smaller differences between peak and trough concentrations.

The authors note that a study by Ye et al (United European Gastroenterology Journal; 2020: 8: 385–386) with 55 patients found that a C-trough >26.6 mcg/mL achieved clinical remission and fecal calprotectin levels <250 mcg/g at week 54 in 79% and 91% respectively compared to 46% and 62% in those with with C-trough <16.4 mcg/g.

These C-trough levels are significantly higher that the median C-trough levels of standard dosing (120 mg biweekly) in a phase 1 dosing RCT which was only 13.3 mcg/mL (S Schreiber et al. Gastroenterology 2018; 154: 1371). The dosing of 180 mg and 240 mg biweekly resulted in C-trough levels of 19.9 mcg/mL and 26.5 mcg/mL respectively.

My take: This study suggests that therapeutic drug monitoring will have different targets with SC-IFX than with IV-SC. SC formulations will offer more convenience. However, more effort will be needed to make sure patients are adherent with therapy in order to achieve optimal outcomes.

Related study: S. N. Hong, J. Hye Song, S. Jin Kim, et al. Inflammatory Bowel Diseases 30 (2024): 517–528. One-Year Clinical Outcomes of Subcutaneous Infliximab Maintenance Therapy Compared With Intravenous Infliximab Maintenance Therapy in Patients With Inflammatory Bowel Disease: A Prospective Cohort Study. In this prospective study with 61 patients, SC IFX switch induced a higher 1-year durable remission rate than continuing IV IFX in patients with IBD during scheduled maintenance therapy.

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REMSWITCH: Infliximab IV to SC Study

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A Buisson et al. Clin Gastroenterol Hepatol 2023; 21: 2338-2346. Open Access! Effectiveness of Switching From Intravenous to Subcutaneous Infliximab in Patients With Inflammatory Bowel Diseases: the REMSWITCH Study

In this study, 133 ot 184 patients in clinical remission agreed to switch to subcutaneous infliximab. Key findings:

  •  At visit 3, a relapse occurred in 10.2% (n = 6 of 59), 7.3% (n = 3 of 38), 16.7% (n = 3 of 18), and 66.7% (n = 10 of 15) (P < .001) of patients receiving 5 mg/kg every 8 weeks (5Q8W), 10Q8W, 10Q6W, and 10Q4W, respectively. 
  • Dose escalation to 240 mg every other week led to recapture clinical remission in 93.3% (n = 14 of 15).
  • Infliximab serum levels increased after the switch (P < .0001) except for patients receiving 10 mg/kg every 4 weeks.
  • Conclusion (borrowed from authors): Switching from intravenous to subcutaneous infliximab 120 mg every other week is safe and well accepted, leading to a low risk of relapse in IBD patients except for those receiving 10Q4W; these patients likely require 240 mg every other week

EV Loftus et al. Clin Gastroenterol Hepatol 2023; 21: 2193. Open Access! Therapeutic Drug Monitoring for Subcutaneous Infliximab? Too Early to Conclude (Editorial) This editorial provides a terrific analysis of the above-mentioned study. A few of the points:

  • Reduced (41.7%) or stable (36.8%) serum levels of IFX after the switch (difference: V1-V0) were associated with higher risk of relapse than increased serum levels (>1 μg/mL; 12.7%; P = .020 and P = .019, respectively)
  • Patients receiving IV infusion of IFX 10Q4W had a higher risk of relapse (odds ratio, 12.4; P = .017). In addition to having significantly higher serum levels than in other IFX IV regimens, this group of patients did not see a rise in IFX concentrations at V1, in contrast to other IFX regimens. 
  • Being overweight increases the clearance of CT-P13 SC, with an increase in clearance of 43.2% for a weight increase from 70 to 120 kg. The presence of antibodies to IFX also increases clearance by 39%. Finally, a decrease in serum albumin level (42 g/L vs 3.2 g/L) increases the clearance by 30.1%. 

My take:

  1. Monitoring IFX levels would be helpful in patients switching from IV to SC administration, especially in higher risk groups (eg. high baseline dosing, positive anti-drug antibodies, low serum albumin, overweight individuals)
  2. My experience with SC biologics has been that there is a much higher rate of non-adherence than with IV infusions. If/when SC biologics are used more often, I will need to implement more intensive followup to assure patients receive both the needed medication and the needed monitoring.

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Infliximab Injections Coming Soon

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  1. L Gianolio et al JPGN 2023; 77(2):p 235-239, August 2023. Effectiveness of Switching to Subcutaneous Infliximab in Pediatric Inflammatory Bowel Disease Patients on Intravenous Maintenance Therapy

Key findings: After switching from IV infliximab to SC 120 mg every other week, 6 of 7 patients remained in clinical remission with no significant changes in laboratory markers and median infliximab trough levels (12.3 µg/mL at baseline; 13.9 and 14.0 µg/mL at 6 and 40 weeks respectively). 

2. Gastroenterology & Endoscopy News (7/31/23) Safety, Efficacy of Subcutaneous Infliximab Supported by Trial

Excerpt:

In this multinational trial, called LIBERTY-CD, the median trough level was 16 mcg/mL, which is higher than that typically associated with IV dosing, according to Dr. Hanauer, who presented the results at Digestive Disease Week 2023 (abstract 1028)… “most professional societies to recommend a trough of 10 mcg/mL,” Dr. Hanauer said….

All patients received induction doses of infliximab by IV at weeks 0, 2 and 6. Those who achieved at least a 100-point reduction in the Crohn’s Disease Activity Index (CDAI), which accounted for 86% of the 396 patients initially enrolled, were randomized in a 2:1 ratio to receive 120 mg of subcutaneous infliximab (CT-P13) or placebo every two weeks.

The proportion of patients meeting the end point of clinical remission, defined on the basis of CDAI, was 62.3% for active therapy and 32.1% for placebo (P<0.0001). The proportion of patients in the active treatment arm achieving an endoscopic response was nearly three times higher than the proportion in the placebo arm (51.1% vs. 17.9%; P<0.0001).

My take: This study shows that SC infliximab (after IV induction) should be effective. A study showing that the SC product is not inferior to the IV dosing would be helpful. It is likely that vedolizumab will receive approval in U.S. for a similar IV induction followed by maintenance subcutaneous therapy in the next year.

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