Therapeutic Drug Monitoring of Infliximab in Acute Severe Ulcerative Colitis
Abstract
:1. Introduction
2. Pharmacokinetics of Infliximab in ASUC
3. Outcomes Associated with Infliximab Pharmacokinetics in ASUC
4. Intensive Infliximab Dosing Strategies in ASUC
5. Specific Threshold Target Concentrations for Infliximab
6. Maintenance Monitoring following Infliximab Salvage Therapy for ASUC
7. Cost-Effectiveness of TDM of Infliximab in ASUC
8. Conclusions and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Author (Year) | Study Design | Population | Number of Subjects | Measurement of IFX Pharmacokinetics | Outcomes |
---|---|---|---|---|---|
Yarur (2016) [23] | Prospective Cross-Sectional | IBD patients on maintenance IFX or adalimumab | 30 (including 6 UC) | Anti-TNF serum concentration and anti-TNF tissue concentration (from colonic and ileal biopsies) | Anti-TNF tissue concentrations correlated with anti-TNF serum concentrations, except in inflamed tissue Ratio of anti-TNF to TNF in tissue was highest in uninflamed tissue and lowest in severely inflamed tissue |
Dotan (2014) [25] | Prospective Observational | IBD patients receiving IFX | 54 patients (25 UC, 25 Crohn’s disease, and 4 indeterminate) with 169 IFX concentrations | IFX trough concentrations and antibodies against IFX prior to IFX infusion | Low albumin, high body weight, and presence of antibodies against IFX were associated with higher IFX clearance |
Fasanmade (2009) [26] | Post-hoc analysis of 2 RCTs (ACT 1 and 2) | Moderate-to-severe UC randomized to IFX 5 mg/kg or 10 mg/kg or placebo | 482 | IFX serum concentrations immediately before and after IFX doses and antibodies against IFX | IFX clearance was higher in patients with antibodies to IFX IFX clearance was inversely correlated with serum albumin |
Brandse (2016) [20] | Prospective Cohort | Anti-TNF naïve moderate–severe UC patients receiving IFX induction therapy | 19 | Serial IFX serum concentrations and antibodies against IFX | IFX nonresponders were more likely to have antibodies against IFX (odds ratio 30.0, 95% CI 2.2–406) Patients with CRP > 50 mg/L at baseline had lower serum IFX concentrations at week 6 compared to patients with lower CRP |
Brandse (2015) [21] | Prospective Cohort | Anti-TNF naïve patients with moderately to severely active UC, initiated on IFX | 30 (26 with severe endoscopic disease) | IFX serum concentration at week 2 and IFX fecal concentration at day 1 from induction | Clinical nonresponders at week 2 had significantly increased fecal IFX levels at day 1 from induction compared to responders (5.01 vs. 0.54 μg/mL) |
Ungar (2016) [30] | Retrospective | Hospitalized steroid-refractory ASUC patients compared to moderately severe UC initiated on IFX | 32 total (including 16 ASUC) | IFX trough concentrations and antibodies to IFX at day 14 from induction | IFX trough concentrations were significantly lower in ASUC patients compared to moderately severe UC patients (7.2 vs. 14.4 μg/mL) |
Author (Year) | Study Design | Population | Number of Subjects | Measurement of IFX Pharmacokinetics | Outcomes Associated with IFX Pharmacokinetics |
---|---|---|---|---|---|
Seow (2010) [22] | Prospective Observational | Steroid-refractory acute moderate-to-severe UC patients initiated on IFX | 115 total (including 42 ASUC) | Detectable serum IFX trough concentration during induction and maintenance periods (found in 39% of subjects) | Higher rates of clinical remission (69% vs. 15%), lower rates of colectomy (7 vs. 55%), and higher rates of endoscopic improvement (76% vs. 28%) were found in patients with detectable troughs compared to those with undetectable troughs |
Arias (2015) [33] | Prospective Observational | UC patients refractory to cyclosporine or immunomodulators, initiated on IFX | 285 total (including 39 ASUC) | Serum IFX level at week 14 of treatment | Serum IFX level > 2.5 μg/mL at week 14 was associated with increased rates of relapse-free survival and colectomy-free survival |
Papamichael (2016) [34] | Retrospective Observational Multicenter | Anti-TNF naïve UC patients with primary nonresponse to IFX induction therapy | 99 total (including 23 ASUC) | Serum IFX levels at weeks 2 and 6 of treatment | Serum IFX level < 16.5 μg/mL at week 2 (hazard ratio 5.6, 95% CI 1.1–27.8) was independently associated with colectomy |
Beswick (2018) [35] | Prospective Observational Pilot | Hospitalized steroid-refractory ASUC patients, initiated on IFX | 24 total (all 24 with ASUC) | Fecal IFX concentration at day 1 post-first dose of IFX | Fecal IFX level > 1 mg/mL at day 1 was associated with lower rates of clinical remission at week 6 (odds ratio 0.04, 95% CI 0.02–0.9) and higher rates of colectomy (odds ratio 176, 95% CI 2.1–14,452) |
Paul (2013) [36] | Prospective Observational | IBD patients receiving IFX who required IFX dose optimization for active disease | 52 total (18 UC, including 10 ASUC) | IFX trough concentrations prior to IFX optimization and at week 8 after optimization; differences in trough concentrations were calculated (called delta IFX) | Delta IFX > 0.5 μg/mL was associated with mucosal healing (sensitivity 0.88, specificity 0.77) |
Papamichael (2016) [37] | Retrospective | UC patients receiving IFX induction | 101 total (including 16 ASUC) | Serum IFX levels at weeks 2, 6, and 14 after induction | Early mucosal healing was associated with increased serum IFX levels at weeks 2 (22.9 vs. 19.3 μg/mL), 6 (17.6 vs. 10.3 μg/mL), and 14 (7.4 vs. 1.5 μg/mL) compared to those without healing |
Battat (2021) [27] | Retrospective | Hospitalized ASUC patients, initiated on IFX | 39 total (all 39 with ASUC) | Baseline calculated IFX clearance using existing formula (that included sex, presence of antibodies to IFX, and serum albumin) | IFX clearance > 0.627 L/day was associated with higher rates of colectomy within 6 months compared to those with lower clearance (61.5% vs. 7.7%) |
Kevans (2018) [38] | Retrospective | Steroid-refractory ASUC patients, initiated on IFX | 36 total (all 36 with ASUC) | IFX clearance using pharmacokinetic modeling (that included serum IFX levels, antibodies to IFX, weight, and serum albumin) | Lower IFX clearance was associated with higher rates of clinical response at week 14 and steroid-free remission at week 54 |
Author (Year) | Study Design | Population | Number of Subjects | Intensive Dosing Strategy | Primary Outcome | Results |
---|---|---|---|---|---|---|
Gibson (2015) [40] | Retrospective Cohort | Hospitalized patients receiving IFX for steroid-refractory ASUC | 50 total (n = 35 standard dosing; n = 15 accelerated dosing | Three induction doses of IFX 5 mg/kg in median 24 days | Colectomy during IFX induction | Significantly decreased rates of early colectomy in the accelerated arm (7% vs. 40%) |
Shah (2018) [42] | Retrospective Cohort with Propensity Score Matching | Hospitalized, IFX-naïve, acute UC patients receiving induction IFX | 146 total (n = 120 standard dose; n = 26 high dose) | 10 mg/kg induction dose of IFX | 30-day colectomy | No significant difference in 30-day colectomy rates between high dose and standard dose groups in the unmatched cohort (15.4% vs. 17.5%) and matched cohort (9.5% vs. 9.5%) |
Chao (2019) [43] | Retrospective Cohort | Hospitalized ASUC patients receiving IFX | 72 total (n = 37 standard dose induction; 35 high dose induction) | 10 mg/kg induction dosing of IFX | Three-month colectomy | No significant difference in three-month colectomy rates between high dose and standard dose groups (14.3% vs. 5.4%) |
Govani (2020) [44] | Retrospective Cohort | Hospitalized ASUC patients receiving IFX | 66 total (n = 33 standard dosing; 33 accelerated dosing) | Two doses of IFX prior to day 14 | 90-day colectomy | No significant difference in 90-day colectomy rates between accelerated dosing and standard dosing groups (30.3% vs. 24.2%) |
Nalagatla (2019) [41] | Retrospective Cohort and Meta-analysis of 7 Retrospective Studies (3 full text, 4 abstract) | Hospitalized patients receiving IFX for steroid-refractory ASUC | Retrospective Cohort: 213 total (n = 132 standard dosing; n = 81 accelerated dosing) Meta-analysis: 617 total (n = 436 standard dosing; n = 181 accelerated dosing) | 10 mg/kg induction dosing of IFX or 5 mg/kg dosing at intervals shorter than weeks 0, 2, and 6 | Retrospective Cohort: in-hospital colectomy Meta-analysis: in-hospital colectomy or one-month colectomy | No significant difference in in-hospital colectomy between accelerated dosing and standard dosing groups (9% vs. 8%) No significant difference in early colectomy between accelerated dosing and standard dosing in the meta-analysis (odds ratio 0.76, 95% CI 0.36–1.61) |
Feuerstein (2020) [10] | Meta-analysis of 5 Observational Studies | Hospitalized patients receiving IFX for steroid-refractory ASUC | Total subjects not given | Shortened interval between IFX dosing (<2 weeks, dose stacking) or 10 mg/kg induction dosing | Short-term risk of colectomy | No significant difference in short-term risk of colectomy between intensive and standard dosing groups (relative risk 1.61, 95% CI 0.74–3.52) |
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Gordon, B.L.; Battat, R. Therapeutic Drug Monitoring of Infliximab in Acute Severe Ulcerative Colitis. J. Clin. Med. 2023, 12, 3378. https://doi.org/10.3390/jcm12103378
Gordon BL, Battat R. Therapeutic Drug Monitoring of Infliximab in Acute Severe Ulcerative Colitis. Journal of Clinical Medicine. 2023; 12(10):3378. https://doi.org/10.3390/jcm12103378
Chicago/Turabian StyleGordon, Benjamin L., and Robert Battat. 2023. "Therapeutic Drug Monitoring of Infliximab in Acute Severe Ulcerative Colitis" Journal of Clinical Medicine 12, no. 10: 3378. https://doi.org/10.3390/jcm12103378