Expert Consensus: New Recommendations for Therapeutic Drug Monitoring

AS Cheifetz et al. Am J Gastroenterol 2021;116: 2014-2025. A Comprehensive Literature Review and Expert Consensus Statement on Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease (published online August 13, 2021)

Key recommendations:

  • The panel agreed that reactive TDM should be used for all biologics for both primary nonresponse and secondary loss of response
  • It was recommended that treatment discontinuation should not be considered for infliximab or adalimumab until a drug concentration of at least 10–15 mg/mL was achieved
  • Consensus was also achieved regarding the utility of proactive TDM for anti–tumor necrosis factor therapy. It was recommended to perform proactive TDM after induction and at least once during maintenance.
  • More data are needed with regard to proactive TDM for biologics other than anti-TNF agents
  • There are no differences in interpreting TDM between originator biologics and biosimilars
  • When considering switching within drug class in case of secondary loss of response to a first anti-TNF drug because of the development of antidrug antibodies, an immunomodulator should be added to a subsequent anti-TNF therapy
  • Low-titer antidrug antibodies can be overcome by treatment optimization (dose escalation, dose interval shortening, and/or addition of an immunomodulator)

My take: This article should help support the practice of proactive TDM and discourage stopping anti-TNF agents until an adequate therapeutic level is achieved.

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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Modeling Trough Levels to Predict Optimal Infliximab Dosing

A recent study for optimizing infliximab  dosing: LE Bauman et al.  2019 Jul 9. pii: izz143. doi: 10.1093/ibd/izz143. [Epub ahead of print]

The authors identified 228 pediatric patients with IBD and developed a pharmocokinetic 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.  Shortening dose interval more reliably achieved therapeutic levels: 5 mg/kg q4 weeks had a target level in 84% and 10 mg/kg q6 weeks had a target level in 80%.

The image above corresponds to Figure 5 in the manuscript.  This figure shows the difference between proactive and reactive dosing strategy.  In the first panel, a higher initial dose prevents suboptimal dosing whereas the second panel shows suboptimal troughs until adjustment of dose after identifying a low trough.  Avoiding low troughs may reduce the likelihood of developing antibodies to infliximab and therapeutic failure

My take: This study and several others indicate that most pediatric patients need either more frequent inflixmab dosing or higher initial doses to achieve therapeutic levels and to improve outcomes.

Non-Adherence Leads to Treatment Escalation and More on Early Infliximab Trough Levels

Briefly noted: JK Carmody et al. AP&T 2019; first published 02 August 2019: Full text link: Longitudinal non‐adherence predicts treatment escalation in paediatric ulcerative colitis

In this cohort of 268 pediatric patients with ulcerative colitis in the prospective PROTECT study, non-adherence to mesalamine was associated with need for treatment escalation.

Key finding:

  • Declining adherence over time strongly predicted treatment escalation (β = −.037, P = .001). By month 6, adherence rate ≤85.7% was associated with treatment escalation.

As noted in a previous blog (Briefly noted: Induction Inflixmab Levels), a recent study (K Clarkston et al. JPGN 2019; 69: 68-74) identified target early infliximab trough levels for infliximab as≥ 29 for week 2 (infusion 2) and ≥18 for week 6 (infusion 3). Below is an associated figure:

Image courtesy of Michael Rosen twitter feed

IBD Update January 2015 (Part 1)

1. From the recent Advances in IBD Conference, Healio Gastroenterology reports on Dr. Baldassano’s update on PLEASE study which examined enteral nutrition in comparison to anti-TNF therapy.  Here’s the link: Enteral Nutrition Outcomes (Thanks to Kipp Ellsworth for this reference)

Here’s an excerpt:

Citing the findings from the Pediatric Longitudinal Study of Semi-Elemental Diet and Stool Microbiome (PLEASE), Baldassano demonstrated that greater mucosal healing was achieved in CD patients on exclusive enteral nutrition compared with partial enteral nutrition therapy. In this prospective cohort study, 38 children received enteral therapy with defined formula diet and 52 controls received anti-TNF-alpha therapy. The enteral nutrition group was further stratified to evaluate mucosal healing on a more restrictive diet; one subgroup received 80% to 90% of total caloric needs from enteral therapy, of which 14% achieved induction of remission at 8 weeks, the other subgroup received 90% to 100% of total caloric needs from enteral therapy, of which 45% achieved remission, and 62% of controls achieved remission.

2. NEJM 2014; 371: 2418-27. This is a case report of a 9-year-old with Crohn’s Disease and pulmonary nodules.  This report serves as a useful review.

3. Standardized use of fecal calprotectin (here’s the link -from KT Park’s Twitter feed):

Fecal calprotectin -use for identifying IBD and for identifying relapse risk

4. Inflamm Bowel Dis 2014; 20: 2247-59. Study examined factors associated with infliximab clearance.  Higher clearance noted with low albumin, high body weight, and the presence of antibodies to infliximab (ATI).  The authors note that higher concentrations with dose escalation are more likely when the dose interval was shortened than by increasing the administered dose.

5. Inflamm Bowel Dis 2014; 20: 2260-65. “Natural History of Perianal Crohn’s Disease After Fecal Diversion.”  Despite greater use of biologics, only 15 of 49 patients reestablished intestinal continuity between 2000-2011.  In this group of 15, only 5 remained reconnected and 3 of these 5 patients had procedures to control sepsis.  The likelihood of sustained intestinal continuity remains low in patients who have required a diverting procedure.

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