Another Study Justifying Higher Infliximab Dosing in Pediatrics

S Lawrence et al. JPGN 2022; 75: 601-607. Optimized Infliximab Induction Predicts Better Long-Term Clinical and Biomarker Outcomes Compared to Standard Induction Dosing

In this retrospective observational cohort study (n=140 children), patients were started on 5 mg/kg/dose during induction. 78 children had “optimized dosing” with an infliximab level drawn prior to 3rd dose. A level <15 mcg/g was considered subtherapeutic. It is noted that combination therapy was much higher in the standard (not optimized) group (95% vs 42%).

Key findings:

  • Combined corticosteroid-free clinical and biomarker remission (CRP < 5 mg/L) was higher in the optimized compared to the standard cohort [65/78 (83%) vs 25/62 (40%), P < 0.001]. Remission rates correlated with trough levels; those in clinical remission had a median level of 3.6 compared to 2.0 in those without clinical remission.
  • The median post-induction trough was higher in the optimized group 4.2 mg/L vs 1.9 mg/L.
  • The optimized group were significantly more likely to achieve a therapeutic level (5 mg/L or greater): 44% vs 18%.

My take:

  1. The “optimized” group was not very well optimized –only 44% had a therapeutic level >5, but still performed much better than the standard group (which more often had combination therapy). This indicates a need to start with higher doses and reinforces the need for therapeutic drug monitoring.
  2. This study further shows that 5 mg/kg dosing is inadequate. In the standard group, even with combination therapy, only 18% achieved therapeutic levels.
  3. This article will be another one to include to try to persuade insurance companies that kids are different and need higher doses of infliximab.
  4. Though inconvenient for families, dosing more frequently is more effective than higher doses for improving trough levels (ie 5 mg/kg q4 wks results in better trough levels than 10 mg/kg q8 wks).

Here are some additional references on this topic (from a recent appeal):

For pediatrics, studies have shown that utilizing dosing of 5 mg/kg/dose results in subtherapeutic dosing in around 80%, especially if low albumin.  This places patients at high risk for developing antibodies to infliximab and complications from Crohn’s disease.

  1. LE Bauman et al Inflamm Bowel Dis 2020 Feb 11;26(3):429-439. Improved Population Pharmacokinetic Model for Predicting Optimized Infliximab Exposure in Pediatric Inflammatory Bowel Disease. The authors identified 228 pediatric patients with IBD and developed a pharmacokinetic model using weight, albumin, sedimentation rate and antibodies to infliximab (ATI) to help predict infliximab dosing that would achieve a therapeutic trough level (>5 mcg/mL). In their study, they also simulated 1000 patients and found that only 24% of patients receiving 5 mg/kg q8weeks achieved a therapeutic level; this increased to 56% for 10 mg/kg q8weeks
  2. Frymoyer A, Piester TL, Park KT. JPGN. 2016;62(5):723-727. Infliximab dosing strategies and predicted trough exposure in children with Crohn’s disease. Only 21% of children in this modeling study achieved a trough level >3 if the albumin was 3 or lower. The goal for trough level is NOW >5.
  3. JM Shapiro et al. JPGN 2016; 62: 867-72. Durability of Infliximab Is Associated With Disease Extent in Children With Inflammatory Bowel Disease.  In this study with 98 pediatric patients, 70% with extensive disease required dose escalation.
  4. Ungar B, Levy I, Yavne Y, et al. Clin Gastroenterol Hepatol. 2016;14(4):550-557.e552. Optimizing Anti-TNF-alpha therapy: serum levels of Infliximab and Adalimumab are associated with mucosal healing in patients with inflammatory bowel diseases. Getting good levels important to achieve healing/remission.
  5. NV Castelle et al. Clin Gastroenterol Hepatol 2022; 20: 465-467. Patients With Low Drug Levels or Antibodies to a Prior Anti-Tumor Necrosis Factor Are More Likely to Develop Antibodies to a Subsequent Anti-Tumor Necrosis Factor. Good levels are associated wtih fewer antibodies to infliximab.

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On a recent trip to Florida, we picked up more than 40 sand dollars on a morning beach walk. This was during a cold snap, at low tide and after a storm.

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IBD Shorts -March 2018

T Piester et al. Inflamm Bowel Dis 2018; 24: 227-34.  Stanford group published data on 49 patients which highlight the utility of a point of care (mobile) infliximab (IFX) dosing calculator:  In their cohort, the IFX calculator recommendations were for IFX dosing escalations in 13% of the 222 calculations.  Overall, the IFX calculator was part of a larger quality initiative (QI) to achieve therapeutic drug levels >5 mcg/mL which occurred in 81% during the QI period.

JC deBruyn et al. JPGN 2018; 66: 268-77. This was a retrospective review of infliximab (IFX) in pediatric Crohn’s disease with 180 children. The authors determined that IFX had good therapeutic durability with 91% remaining on IFX after 2 years of treatment.

FS Macaluso et al. Inflamm Bowel Dis 2018; 24: 394-401. In this 2-year study, among 630 patients, 46 had a modestly-dosed immunomodulator added to anti-TNF therapy due to loss of response (31 to IFX or biosimilar, 10 with adalimumab, and 5 with golimumab).  This resulted in a steroid-free remission in 15 (32.6%) and a clinical response in 6 (13.0%). The immunomodulators were azathioprine in 15, 6-mercaptopurine in 5, methotrexate in 20, and mycophenolate mofetil in 6. The median doses for immunomodulators were 1.64 mg/kg/day, 0.84 mg/kg/day, 15.6 mg/week, and 1500 mg/day respectively.

C Reenaers et al. Clin Gastroenter Hepatol 2018; 16: 234-43. This retrospective study examined 7-year outcomes from a STORI cohort of 115 adults with Crohn’s disease (CD) with combination therapy who had infliximab withdrawal after achieving sustained remission. Among those restarting infliximab, treatment failed in 30.1%; 70.2% “had no failure of de-escalation strategy.” Major complicatins occurred in 18.5% of patients. Risk factors for failure included anemia (Hgb <12.5), increased white blood cell count >5.0, and upper GI location of CD.

VM Merrick et al. JPGN 2018; 66: 274-80.  This UK “real-life” review of 37 centers and 524 patients (429 with Crohn’s disease) found a remarkably poor rate of documentation.  They could determine the remission rates in only 71 of these patients (65% 46 of 71).  Thus, in the real-world, presumably in adults and children, most institutions do not know their remission rates.  While the determination of remission still relies on imperfect measures, the centers who participate in ImproveCareNow have high documentation rates –this is also a real-world experience as more than 29,000 patients and more than 900 pediatric GI doctors participate.