Proactive Therapeutic Drug Monitoring -Different Time Points

Yesterday’s post outlined expert recommendations for proactive therapeutic drug monitoring (pTDM).  Today’s post reviews a study (NV Casteele et al. Clin Gastroenterol Hepatol 2019; 17: 1814-21) which identifies optimal levels at earlier time points. The authors note that “higher infliximab (IFX) concentrations during induction therapy  are correlated with long-term relapse-free and colectomy-free survival.”

The authors analyzed data from 484 patients with active ulcerative colitis (UC) from two double-blind, placebo-controlled, parallel group studies: ACT-1 and ACT-2.

Key findings:

  • IFX levels ≥18.6 mcg/mL at week 2, ≥10.6 mcg/mL at week 6, and ≥34.9 mcg/mL at week 8 were associated with Mayo endoscopic scores (MES) of ≤1 at week 8.
  • IFX level of ≥5.1 mcg/mL at week 14 was associated with MES of ≤1 at week 30
  • IFX level of ≥6.7 mcg/mL at week 14 was associated with MES of 0 at week 30

My take: In pediatric patients receiving monotherapy with an anti-TNF agent, checking earlier levels (week 6, week 8, or week 10) may help avoid low troughs which are associated with a higher likelihood of treatment failure.  This study provides guidance on target levels at earlier time points.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  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.

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Appropriate Proactive Therapeutic Drug Monitoring

This blog post and tomorrow’s post highlights two articles on proactive therapeutic drug monitoring (pTDM) for inflammatory bowel disease.  The first article (K Papmichael et al.  Clin Gastroenterol Hepatol 2019; 17: 1655-68) summarizes a meeting of 13 international IBD specialists who reached consensus on 24 statements after a review of the literature.

Full Text Link:  Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases

Key Recommendations:

  • For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics.
  • Reactive TDM was appropriate for all biologic agents both for primary non-response and secondary loss of response

Background/Rationale for pTDM:

  • “Numerous studies have demonstrated a positive correlation between serum biologic drug.concentrations and favorable therapeutic outcomes”
  • “Low or undetectable drug concentrations can lead to immunogenicity and treatment failures”
  • “TDM…is an important tool for optimizing biologic therapy…Data suggest that pTDM, with drug titration to a target trough concentration, performed in patients with clinical response/remission can also improve the efficacy of anti-TNFs”

Table 4  Scenarios of Applying Therapeutic Drug Monitoring of Biological Therapy in Patients With Inflammatory Bowel Disease

1-4: Anti-TNFs:

  • It is appropriate to order drug/antibody concentration testing in responders at the end of induction for all anti-TNFs.
  • It is appropriate to order drug/antibody concentration testing at least once during maintenance for patients on all anti-TNFs.
  • It is appropriate to order drug/antibody concentration testing of anti-TNFs at the end of induction in primary non-responders.
  • It is appropriate to order drug/antibody concentration testing for all anti-TNFs in patients with confirmed secondary loss of response.

5-8: Vedolizumab -agreement only on ordering TDM in non-responders or those with loss of response

9-12: Ustekinumab  -agreement only on ordering TDM in non-responders or those with loss of response

From Table 5: Biological Drug Concentrations and Anti-Drug Antibodies When Applying Therapeutic Drug Monitoring in Inflammatory Bowel Disease

  • Infliximab: 15. In the presence of adequate trough drug concentrations, anti-drug antibodies are unlikely to be clinically relevant.
  • Infliximab: 19. The minimal trough concentration for infliximab post-induction at week 14 should be greater than 3 μg/mL, and concentrations greater than 7 μg/mL are associated with an increased likelihood of mucosal healing.
  • Adalimumab: 22. The minimum drug concentration at week 4 for adalimumab should at least be 5 μg/mL. Drug concentrations greater than 7 μg/ml are associated with an increased likelihood of mucosal healing.
  • Certolizumab: 24 & 25: The minimum concentrations for certolizumab pegol at week 6 should be greater than 32 μg/mL and 15 μg/mL during maintenance.
  • Golimumab 26 & 27: The minimum drug concentration at week 6 for golimumab should at least be 2.5 μg/mL and 1 μg/mL.during maintenance

My take: This article provides extensive literature to reinforce their recommendations.  Most of the trough levels mentioned are minimum levels that need to be achieved.

 

Can Therapeutic Drug Monitoring with Monotherapy Achieve Similar Results as Combination Therapy for IBD?

A recent retrospective study (S Lega et al. Inflamm Bowel Dis 2019; 25: 134-41) suggests that proactive therapeutic drug monitoring (pTDM) with infliximab (IFX) helps achieve similar outcomes as combination therapy (with immunomodulator) in patients with inflammatory bowel disease.

Before reviewing the key findings, it is important to emphasize a few crucial limitations/methods:

  • The study enrolled 83 patients; only 16 received were in the monotherapy pTDM group.
  • This was a retrospective study
  • The authors utilized TDM at week 10.  If the IFX level was <20 mcg/mL, the dose and frequency of infliximab were both adjusted. If the level was between 20 & 25, either the frequency was adjusted or no adjustment, and if the level was >25, then no adjustment in dosing was performed.

Key findings:

  • The frequency of infliximab discontinuation with mono therapy in those with pTDM was lower than in those with ‘standard of care’ TDM (P=0.04) but did not differ from patients receiving combination therapy
  • Overall 9 of the 83 patients (11%) discontinued IFX during the 1-year study

In the discussion, the authors suggest that week 14 TDM may be suboptimal as this is the first time patients have an 8-week interval.

My take: The jury is out with regard to whether pTDM can negate the need for combination therapy  –a prospective trial is needed; however, the idea of getting TDM a bit earlier is intriguing, particularly as it has been shown that a high percentage of pediatric patients are receiving an insufficient dose of infliximab (Is Standard Infliximab Dose Tool Low in Pediatrics?)

Key words: 10 weeks, therapeutic drug monitoring, infliximab, trough

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  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.

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Is There Good Evidence for Proactive Drug Monitoring of Anti-TNF Therapy?

A recent clinical review (X Roblin et al. Inflamm Bowel Dis 2018; 24: 1904-9) examines the utility of proactive drug monitoring of anti-TNF therapy in inflammatory bowel disease.

The authors note that several observational trials suggested that proactive drug monitoring would help optimize the effect of anti-TNF therapy, especially infliximab. However, two randomized controlled clinical trials, TAXIT (n=273) and TAILORIX (n=122), were not able to show long-term benefit from proactive therapeutic monitoring.

At the same time, the authors note that a recent trial (Ungar B et al. Clin Gastroenterol Hepatol 2016; 14: 550-7, e2) has shown that infliximab trough levels >5 mcg/mL and adalimumab levels >7.2 mcg/mL identified mucosal healing with 85% specificity. Higher cutoffs showed only minimal further increase in mucosal healing rates.

My take: To this point, controlled trials have not shown that proactive drug monitoring of anti-TNF therapy is beneficial; this review explains the design and limitations of these studies.  My personal view is that more studies are needed to know if proactive drug monitoring is worthwhile.  Proactive drug monitoring may be more useful in children/adolescents than adults due to much greater variation in size and dosing.

A recent commentary on therapeutic drug monitoring (from KT Park Twitter Feed): Therapeutic Targets in IBD

Related blog posts:

 

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NASPGHAN Postgraduate Course 2017 (Part 4): Therapeutic drug monitoring, Anti-TNF management, Postoperative Crohn’s disease

This blog entry has abbreviated/summarized these presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

Here is a link to postgraduate course syllabus: NASPGHAN PG Syllabus – 2017

Therapeutic Drug Monitoring

Andrew Grossman  Children’s Hospital of Philadelphia

The topic of therapeutic drug monitoring, both reactive and proactive, has been discussed numerous times on this blog.  This talk provided a good review of this topic.

Key points:

  • Greatest predictor of infliximab treatment failure was a low infliximab (<0.9 mcg/mL at anytime or <2.2 mcg/mL at 14 weeks) (Castelle et al Am J Gastro 2013; 108: 962-71)
  • Low level antibodies to infliximab may be transient in ~28% and may be overcome with escalation of therapy
  • Tissue levels of infliximab (and other agents) may be inadequate despite good serum levels

What if anti-TNF fails

Maria Oliva-Hemker   Johns Hopkins University School of Medicine

Key points:

  • Discussed prevalence of problem with anti-TNF failures and main options: vedolizumab, ustekinumab, and surgery
  • Vedolizumab can take a while to work, particularly for Crohn’s disease
  • Limited data in pediatrics for these newer agents
  • Ustekinumab has some preliminary data indicating benefit with anti-TNF induced psoriaform rashes
  • Newer agents also likely to need therapeutic drug monitoring
  • Overall, ustekinumab and vedolizumab have good safety profiles at this point

 

Prevention of postoperative Crohn’s disease

Miguel Regueiro   University of Pittsburgh

  • Rationale for postoperative preventative treatment: high rate of recurrent disease which can be silent for several years despite progressive damage to GI tract
  • Large study (PREVENT) to compare infliximab and placebo after surgery.  Primary endpoint was clinical recurrence (was endpoint demanded by FDA) even though clinical recurrence can be a late finding.  Endoscopic recurrence rate was a secondary endpoint.

Dr. Regueiro’s approach

  • Low risk patient –repeat scope at 6 months post-op, then every 1-3 yrs if no disease and Rx with anti-TNF or immunomodulator in those with endoscopic recurrence
  • Moderate risk patient -possible use of thiopurine or use the ‘low risk’ approach
  • High risk patient-combination therapy and if doing well for several years, consider monotherapy
  • In pediatrics, the postoperative management is unclear due to difficulty with risk stratification.  If postoperative treatment is not given, consider colonoscopy 3-4 months afterwards and treat if recurrence.  Then could use calprotectin every 3 months to monitor and when >50, likely will need to be treated

PREVENT Trial Data: