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This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.

REMICADE® (infliximab)

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Measuring Infliximab Trough Levels During REMICADE Treatment

Last Updated: 11/21/2024

Summary

The company cannot recommend any practices, procedures, or usage that deviate from the approved labeling.
Please refer to local labeling for relevant information regarding this topic.
Janssen Biotech, Inc. has no recommendations on an established therapeutic level of infliximab. There is no consensus on the necessity of taking infliximab serum concentration levels during therapy and no recommendations on when during therapy to take serum infliximab concentration levels.
Various data have been published in the medical literature specifically focused and aimed at measuring serum infliximab trough levels during REMICADE treatment and comparing the trough levels with reported efficacy outcomes (studies without a statistical analysis are not summarized here). Additionally, only study designs which included randomization of patients are summarized in the following tables.¹^-¹²

CLINICAL DATA

Crohn’s Disease (CD)

Patients with CD: Randomized Studies¹^-⁵

Study	Study Design	REMICADE Dose Regimen	Primary Endpoint or Aim of Study	Infliximab Trough Concentration Relation to Efficacy Outcomes
Bossuyt et al (2021)¹	Subanalysis of data from the TAILORIX trial (multicenter randomized controlled trial) including patients having ≥1 magnetic resonance enterography (MRE)	5 mg/kg REMICADE infusion at weeks 0, 2, and 6 (induction phase), then randomized to receive 1 of 3 regimens, with dose adjustment based on either clinical symptoms only or on a combination of clinical symptoms, Creactive protein (CRP), fecal calprotectin (FCP), and infliximab trough levels	To assess the influence of the pharmaco-dynamics of infliximab on radiologic response and remission in patients with CD based on MRE assessments at baseline and at week 54 after initiation of infliximab therapy	Patients having both baseline and week 54 MREs (n=31) were included. Radiologic remission (magnetic resonance index of activity [MaRIA] score <7) at week 54 was correlated with infliximab trough levels at week 14 (cutoff value, 7.8 µg/mL; P=0.049). Radiologic response (MaRIA score <11) at week 54 was correlated with infliximab trough levels at week 14 (cutoff value, 7.8 µg/mL; P=0.048) and with continuous pharmacologic response (infliximab trough levels >5.0 µg/mL at all time points; P=0.034). Patients who were in the highest quartile of infliximab trough levels at week 14 (≥8.55 µg/mL) exhibited the highest percentage of radiologic response (P=0.03) and remission (P=0.06) at week 54. At week 14, a numerical difference in median infliximab trough levels was observed in patients who achieved both endoscopic and radiologic remission (8.5 µg/mL; interquartile range [IQR], 4.6-10.4) vs those who achieved only endoscopic remission (5.8 µg/mL; IQR, 2.7-6.5) (P=0.095); this was not observed at week 54 (P=0.35). In a subgroup of patients (n=21) who had a dose escalation during maintenance therapy with infliximab, continuous pharmacologic response (infliximab trough levels >7 µg/mL at all time points) was associated with radiologic response (P=0.039) and remission (P=0.019). No difference in radiologic response (P=0.76) or remission (P=0.59) rates was noted between patients with and without dose modifications during maintenance therapy.
Papamichael et al (2020)²	Post hoc analysis of the ACCENT 2 trial (multicenter, randomized, double-blind, placebo-controlled trial)	5 mg/kg REMICADE infusion administered at weeks 0, 2, and 6 (induction therapy). At week 14, patients with response were randomized to receive 5 mg/kg infliximab or placebo at weeks 14, 22, 30, 38, and 46. Nonresponders were randomized to a maintenance regimen of infliximab or placebo. From week 22, patients with loss of response who were receiving maintenance therapy with placebo and infliximab could crossover to maintenance therapy with 5 mg/kg and 10 mg/kg infliximab, respectively.	To evaluate the correlation between therapeutic outcomes and infliximab serum concentrations during both induction and maintenance therapy in patients with fistulizing CD	Overall, 282 patients who received induction therapy were included. Serum infliximab concentrations at weeks 2, 6, and 14 were numerically higher in patients with fistula response than those in patients without fistula response. In a multivariable analysis, the only variable associated with fistula response at week 14 was serum infliximab concentration at week 14 (odds ratio [OR], 1.16; 95% confidence interval [CI], 1.021.32; P=0.019). Serum infliximab concentrations at week 6 (P=0.021) and week 14 (P=0.009) were significantly higher in patients with fistula response at week 54 than those in patients without fistula response. Serum infliximab concentrations at week 6 (P=0.038) and week 14 (P=0.002) were significantly higher in patients with complete fistula response at week 14 than those in patients without complete fistula response. In a multivariable analysis, variables associated with complete fistula response at week 14 included infliximab concentration at week 14 (OR, 1.18; 95% CI, 1.03-1.35; P=0.019), perianal fistula location (OR, 2.60; 95% CI, 2.19-5.68; P=0.016), and draining fistulas >1 at baseline (OR, 0.30; 95% CI, 0.18-0.50; P<0.001). Serum infliximab concentrations at week 6 were significantly higher (P=0.048) in patients with complete fistula response at week 54 than those in patients without complete fistula response. Serum infliximab concentrations at week 14 were significantly higher (P=0.004) in patients with CRP normalization than those without CRP normalization. In a multivariable analysis, infliximab concentration at week 14 (OR, 1.46; 95% CI, 1.18-1.80; P<0.001) and perianal fistula location (OR, 3.95; 95% CI, 1.22-12.78; P=0.022) were the only variables associated with CRP normalization at week 14; no variables were associated with CRP normalization at week 54. Serum infliximab concentrations at week 30 (P=0.030), week 46 (P=0.033), and week 54 (P=0.006) were significantly higher in patients with CRP normalization at week 54 than those in patients without CRP normalization. Serum infliximab concentrations at week 6 (P=0.001) and week 14 (P<0.001) were significantly higher in patients with composite remission at week 14 than those in patients without composite remission. In a multivariable analysis, infliximab concentration at week 14 was the only variable associated with composite remission (OR, 2.32; 95% CI, 1.55-3.49; P<0.001). Serum infliximab concentrations at week 14 (P=0.049) and week 54 (P=0.038) were significantly higher in patients with composite remission at week 54 than those in patients without composite remission. In a multivariable analysis, infliximab concentration at week 14 was the only variable associated with composite remission at week 54 (OR, 2.05; 95% CI, 1.10-3.82; P=0.024).
Reinisch et al (2015)³	Post-hoc analysis of patients receiving REMICADE therapy during the SONIC trial (multicenter, randomized, double-blind, active-controlled trial comparing REMICADE monotherapy vs REMICADE plus azathioprine vs azathioprine alone)⁴	5 mg/kg REMICADE infusion at weeks 0, 2, and 6, then every 8 weeks, with placebo capsules (REMICADE monotherapy; n=96); 5 mg/kg REMICADE infusion at weeks 0, 2, and 6, then every 8 weeks, with azathioprine 2.5 mg/kg/day capsules (REMICADE combination therapy; n=107)	To investigate factors associated with corticosteroid-free remission at week 50 (CSFR50) and mucosal healing at week 26 (0 ulcers and/or erosions; MH26)	CSFR50 was observed in 55.2% (n=53) and 65.4% (n=70) of patients who received REMICADE monotherapy and combination therapy, respectively. Median week 30 trough serum infliximab concentration (SIC30) was significantly higher in patients who achieved CSFR50 (OR, 3.1; 95% CI, 1.2-6.0 µg/mL; n=123) than in patients who did not achieve CSFR50 (OR, 1.7; 95% CI, 0.1-3.7 µg/mL; n=80; P=0.002). Patients given combination therapy had higher trough SIC30s than those given monotherapy. Among patients who received monotherapy, the median trough SIC30 was significantly higher in patients who achieved CSFR50 than for those who did not (2.14 and 0.80 µg/mL, respectively; P=0.006); this was not seen in patients who received combination therapy (3.56 and 3.54 µg/mL, respectively; P=0.31). In patients with increased baseline levels of CRP (≥8.0 mg/L; n=120), trough SIC30 of ≥3.0 µg/mL was significantly associated with CSFR50 (OR, 3.20; 95% CI, 1.38-7.42; P=0.007). MH26 was observed in 46.4% (26/56) and 65.7% (44/67) of patients evaluable for mucosal healing who received REMICADE monotherapy and combination therapy, respectively. In patients evaluable for mucosal healing, trough SIC30 of ≥3.0 µg/mL was significantly associated with MH26 (OR, 3.34; 95% CI, 1.53-7.28; P=0.002).
Cornillie et al (2014)⁵	Post-hoc analysis of data from the ACCENT 1 trial (multicenter, randomized, double-blind trial) ACCENT 1 trial included 2-week induction and 52-week maintenance treatment. infliximab serum levels were measured at weeks 0, 2, 6, 14, 22, 30, 38, 46, and 54.	5 mg/kg at 0, 2, and 6 weeks, with a maintenance dose among week 2 responders of 5 mg/kg every 8 weeks (n=192) or 10 mg/kg every 8 weeks (n=193)	Association between serum infliximab postinduction trough levels and CRP with durable sustained clinical response (defined as a decrease of ≥70 points and ≥25% reduction from baseline in the Crohn’s Disease Activity Index [CDAI] score)	At week 14, median serum infliximab trough levels in patients with and without sustained clinical response were 4.0 vs 1.9 mcg/mL (P=0.0331) for the 5 mg/kg group and 4.1 vs 1.9 mcg/mL (P=0.1109) for the 10 mg/kg group, respectively. Among patients receiving concomitant immunomodulators, median serum infliximab trough level at week 14 for the 5 mg/kg group was significantly higher in patients with sustained clinical response compared to that in patients without sustained response, 4.6 vs 1.7 mcg/mL (P=0.0047), respectively. No significant difference was observed for the 10 mg/kg group. Sustained clinical response through week 54 for the 5 mg/kg group was achieved in 18% of patients with serum infliximab trough levels <3.5 mcg/mL vs 39% of patients with trough levels ≥3.5 mcg/mL (P=0.0042). Overall, serum infliximab trough levels in the 5 mg/kg and 10 mg/kg groups were mostly overlapping between patients with and without clinical response: the difference was significant at weeks 6, 14, and 22 for the 5 mg/kg group and at weeks 22 and 38 for the 10 mg/kg group.

Ulcerative Colitis (UC)

Patients with Ulcerative Colitis (UC): Randomized Study⁶

Study	Study Design	REMICADE Dose Regimen	Primary Endpoint or Aim of Study	Infliximab Trough Concentration Relation to Efficacy Outcomes
Kobayashi et al (2016)⁶	Multicenter, prospective, randomized, double-blind, placebo-controlled study as part of a phase 3 trial	5 mg/kg at 0, 2, and 6 weeks. Patients with evidence of a response by week 8 continued treatment at weeks 14 and 22 (n=104; n=82 in post-hoc analysis)	Clinical response at week 8 (defined as a decrease from baseline in the Mayo score of ≥30% and ≥3 points, accompanied by a decrease in the rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1)	At week 8, the clinical response rate was significantly higher in the infliximab group than the placebo group (54.8% [57/104] vs 35.6% [37/104], P=0.005). Week 2 trough level ≥20.7 µg/mL was significantly associated with a 14-week clinical activity index remission (OR 2.75; 95% CI 1.13-6.93, P=0.025). In multiple logistic regression analysis, the week 2 trough level-to-clinical activity index ratio (TL/CAI, OR 8.07; 95% CI 2.84-27.07, P<0.001) was an independent factor correlating with 14-week clinical activity index remission. The week 2 trough level and TL/CAI were also significantly associated with 30-week mucosal healing (P=0.032 for week 2 trough level; P=0.003 for week 2 TL/CAI).

CD and UC

Patients with CD and Patients with UC: Randomized Studies⁷^-⁹

Study	Study Design	REMICADE Dose Regimen	Primary Endpoint or Aim of Study	Infliximab Trough Concentration Relation to Efficacy Outcomes
Vande Casteele et al (2015)⁷	Randomized, double-blind, double-arm, prospective study	First, the REMICADE dose was optimized to have an infliximab trough concentration within the interval of 3-7 µg/mL according to a treatment algorithm (optimization phase; range, REMICADE 5 mg/kg or 10 mg/kg every 4-12 weeks). Patients who achieved an infliximab trough concentration within the optimal interval were assigned to either: REMICADE dosing based on clinical symptoms and CRP (n=123), or to continue dosing based on infliximab trough concentration (n=128) (maintenance phase).	The proportion of patients in each group in clinical (Harvey-Bradshaw index ≤4 for CD and partial Mayo score ≤2 with no individual subscore >1 for UC) and biological (CRP concentration of ≤5 mg/L) remission at year 1 of optimization	A total of 263 patients (178 with CD and 85 with UC) with stable responses to maintenance REMICADE therapy were included in the study. At screening, 115 of 263 (43.7%) patients had an infliximab trough concentration of 3-7 µg/mL. Of 76 patients with trough concentrations <3 µg/mL, 69 patients (91%) achieved trough concentrations of 3-7 µg/mL after dose escalation. This resulted in a higher proportion of CD patients in remission than before dose escalation (88% vs 65%; P=0.020) and a decrease in the median concentration of CRP, compared with before the dose increase (3.2 vs 4.3 mg/L; P<0.001); these changes were not seen in UC patients. Of 72 patients with trough concentrations >7 µg/mL, 67 patients (93%) achieved trough concentrations of 3-7 µg/mL after dose reduction. This resulted in a 27.9% reduction in drug cost from before dose reduction (P<0.001). Sixty-six percent (n=81/123) of patients whose dosing was based on clinical features and 69% (n=88/128) whose dosing was based on trough concentration achieved remission (P=0.686). Disease relapsed in 21 patients who received clinically based dosing (17%) and 9 patients who received concentration-based dosing (7%; P=0.018).
Steenholdt et al (2011)⁸	Randomized, single-blind, single-arm, retrospective study	5 mg/kg at 0, 2, and 6 weeks, then every 8 weeks (n=106)	Determining cutoff levels for infliximab and anti-infliximab antibody concentrations associated with clinical response to REMICADE maintenance therapy (cutoff values analyzed not displayed in this table)	CD: Infliximab trough levels were significantly higher in patients with maintained response to REMICADE maintenance therapy (median 2.8 mcg/mL, n=48) vs patients with loss of response to REMICADE maintenance therapy (median 0 mcg/mL, n=21; P<0.0001). UC: Infliximab trough levels were significantly higher in patients with maintained response (median 3.8 mcg/mL, n=5) vs patients who had lost response to REMICADE maintenance therapy (median 0 mcg/mL, n=8; P=0.0083).
Vande Casteele et al (2012)⁹	Randomized, single arm, prospective study	5 mg/kg at 0, 2, and 6 weeks, then every 8 weeks (n=275)	Clinical and biological (CRP <5 mg/L) remission rates at 1 year	Patients with trough level <3 mcg/mL had a significantly higher CRP (median 2.7 mg/L) vs patients with a trough level between 3 and 7 mcg/mL (median 1.5 mg/L; P<0.001) and patients with a trough level >7 mcg/mL (median 1.2 mg/L; P<0.01).

Rheumatoid Arthritis (RA)

Patients with RA: Randomized Studies¹⁰^,¹¹

Study	Study Design	REMICADE Dose Regimen	Primary Endpoint or Aim of Study	Infliximab Trough Concentration Relation to Efficacy Outcomes
Takeuchi et al (2009)¹⁰	Randomized, double-blind, single-arm, prospective study	3 mg/kg REMICADE infusion at weeks 0, 2, and 6, then were randomly assigned to be administered 3, 6, or 10 mg/kg REMICADE every 8 weeks from week 14-46 (n=307)	Mean American College of Rheumatology improvement (ACR-N) at week 54	Higher serum infliximab trough level in patients demonstrated a better clinical response or greater inhibition of progression of joint damage. Patients with trough level <0.1 mcg/mL (n=66/271) showed most progression of joint damage (none showed improvement) and patients with trough level >10.0 mcg/mL (n=22/271) showed no cases of progression.
St. Clair et al (2002)¹¹	Randomized, double-blind, placebo-controlled, prospective study	3 mg/kg every 4 weeks (n=86); 3 mg/kg every 8 weeks (n=86); 10 mg/kg every 4 weeks (n=86); 10 mg/kg every 8 weeks (n=86)	Trough serum levels of infliximab and magnitude of American College of Rheumatology response	Highest percent of subjects with less than an American College of Rheumatology 20% response was found in the group with undetectable infliximab trough level (<0.1 mcg/mL; P<0.001) Highest percent of subjects with American College of Rheumatology 50% and American College of Rheumatology 70% responders had the highest infliximab trough level (>1 to ≤10 and >10 mcg/mL; P<0.001) Some subjects achieved an ACR50 or ACR70 response despite undetectable trough serum levels of infliximab (<0.1 mcg/mL).

Ankylosing Spondylitis (AS)

Patients with AS: Randomized Study¹²

Study	Study Design	REMICADE Dose Regimen	Primary Endpoint or Aim of Study	Infliximab Trough Concentration Relation to Efficacy Outcomes
Krzysiek et al (2009)¹²	Randomized, open-label, single-arm, prospective study	At inclusion visit (week 0) patients randomized to either 5 mg/kg at weeks 4, 6, 10, and then every 6 weeks (continuous treatment), or 5 mg/kg at weeks 4, 6, and 10, then upon symptom recurrence (on-demand treatment) (N=247)	Comparison of the circulating infliximab concentration and the presence of clinical symptoms in patients with continuous REMICADE treatment of after treatment interruption	In the continuous treatment group (n=93), treatment failure was not associated with a low circulating concentration of infliximab (either during early treatment or at 1 year). 39.2% (n=11/28) of nonresponders had an infliximab trough concentration of >10 mcg/mL at week 52, and 13.8% (n=9/65) of responders had an infliximab trough concentration of <1 mcg/mL.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 17 August 2023.

Summarized in this response are relevant data from randomized studies that measured infliximab trough levels during REMICADE treatment and compared the levels with reported efficacy outcomes. Studies without a statistical analysis are not summarized in this response. Additionally, only study designs which included randomization of patients are summarized in this response.

References

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1	Bossuyt P, Dreesen E, Rimola J, et al. Infliximab exposure associates with radiologic evidence of healing in patients with Crohn’s disease. 2021;19(5):947-954.
2	Papamichael K, Casteele NV, Jeyarajah J, et al. Higher postinduction infliximab concentrations are associated with improved clinical outcomes in fistulizing Crohn's disease: an ACCENT-II post hoc analysis. Am J Gastreonterol. 2021;116(5):1007-1014.
3	Reinisch W, Colombel JF, Sandborn WJ, et al. Factors associated with short- and long-term outcomes of therapy for Crohn's disease. Clin Gastroenterol Hepatol. 2015;13(3):539-547.
4	Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010;362:1383-1395.
5	Cornillie F, Hanauer SB, Diamond RH, et al. Postinduction serum infliximab trough level and decrease of C-reactive protein level are associated with durable sustained response to infliximab: a retrospective analysis of the ACCENT I trial. Gut. 2014;63(11):1721-1727.
6	Kobayashi T, Suzuki Y, Motoya S, et al. First trough level of infliximab at week 2 predicts future outcomes of induction therapy in ulcerative colitis-results from a multicenter prospective randomized controlled trial and its post hoc analysis. J Gastroenterol. 2016;51(3):241-251.
7	Vande Casteele N, Ferrante M, Van Assche G, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015;148(7):1320-1329.
8	Steenholdt C, Bendtzen K, Brynskov J, et al. Cut-off levels and diagnostic accuracy of infliximab trough levels and anti-infliximab antibodies in Crohn's disease. Scandinavian Journal of Gastroenterology. 2011;46(3):310-318.
9	Vande Casteele N, Compernolle G, Ballet V, et al. Results on the optimisation phase of the prospective controlled trough level adapted infliximab treatment (TAXIT) trial [abstract]. Gastroenterology. 2012;142(5):1159. S1211-S1212.
10	Takeuchi T, Miyasaka N, Inoue K, et al. RISING study. Impact of trough serum level on radiographic and clinical response to infliximab plus methotrexate in patients with rheumatoid arthritis: results from the RISING study. Modern Rheumatology. 2009;19(5):478-487.
11	St Clair, EW, Wagner CL, Fasanmade AA, et al. The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis & Rheumatism. 2002;46(6):1451-1459.
12	Krzysiek R, Breban M, Ravaud P, et al. Circulating concentration of infliximab and response to treatment in ankylosing spondylitis: results from a randomized control study. Arthritis & Rheumatism. 2009;61(5):569-576.