Expert Consensus: New Recommendations for Therapeutic Drug Monitoring

AS Cheifetz et al. Am J Gastroenterol 2021;00:1–12. 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.

Related blog posts:

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.

For the Next Insurance Appeal: Therapeutic Drug Monitoring in Adalimumab Treatment (Pediatrics) & Satire on Prior Authorizations

There is a lot of data supporting the use of therapeutic drug monitoring (TDM) for anti-TNF agents. A recent study (MJ Kim et al. JPGN 2021; 72: 870-876. Therapeutic Drug Monitoring of Adalimumab During Long-term Follow-up in Paediatric Patients With Crohn Disease) adds to this data and supports increased adalimumab (ADL) dosing if below target values.

In this prospective study of 31 pediatric patients with Crohn’s disease, the authors found correlations between ADL values and the endpoints of clinical remission (CR) and mucosal healing (MH). The authors checked TLs at 4 months, 1, 2, and 3 years. Key findings:

  • The median trough levels (TLs) of ADL were higher in patients in CR (7.6 ± 3.5 μg/mL) than in patients with active disease (5.1 ± 2.2 μg/mL).
  • ADL TLs were significantly higher in patients who achieved MH than in those who did not (14.2 ± 7.6 vs 7.8 ± 5.2 μg/mL). 
  • The optimal cut-point for predicting MH at 1 year of ADL treatment was 8.18 μg/mL
  • MH was noted in 42% at 4 months and 55% at 1 yr; CR was noted in 90% at 4 months and 84% at 1 yr. ADL treatment was associated with positive effects on growth indicators as well.

The authors discuss TDM for anti-TNF therapy, noting that for infliximab, the AGA recommends values >5 mcg/mL and the ACG >7.5 mcg/mL. There are fewer studies of ADL TDM -prior studies have indicated goals of >5.8, >7.1, >8, and >8.1; thus, this study is in agreement with these prior studies.

My take: This study further supports the value of TDM; better drug levels correlate with better outcomes.

Related blog posts:

Fort Jefferson, Dry Tortugas. The fort has reportedly 16 million bricks (I didn’t confirm this figure).

More satireOn Prior Authorizations:

Real-World Experience with Proactive Therapeutic Drug Monitoring in Inflammatory Bowel Disease

A recent large retrospective pediatric study provides further evidence that therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) results in better clinical outcomes. One of my partners, Chelly Dykes, is a coauthor and leads our ImproveCareNow team.

JL Lyles et al. Inflamm Bowel Dis 2021; 27: 482-492. Effect of a Practice-wide Anti-TNF Proactive Therapeutic Drug Monitoring Program on Outcomes in Pediatric Patients with Inflammatory Bowel Disease

This single center implemented a practice wide TDM approach in 2014. This study compared a historical pre-TDM group (n=108) to the TDM group (n=206). The primary outcome was sustained clinical remission (SCR22-52), defined as physician global assessment (PGA) of inactive from 22 to 52 weeks and off corticosteroids at 52 weeks. Key findings:

  • The SCR22-52 was achieved in 42% of pre-TDM and 59% of TDM patients (risk difference, 17.6%; 95% CI, 5.4–29%; P = 0.004)
  • The TDM group had an increased adjusted odds of achieving SCR22-52 (odds ratio, 2.03; 95% CI, 1.27–3.26; P = 0.003)
  • The adjusted risk of developing high titer antidrug antibodies (ADAs) was lower in the post-TDM group (hazard ratio, 0.18; 95% CI, 0.09–0.35; P < 0.001)
  • The SCBR22-52 (which was defined by normal CRP along with SCR22-52) was 24.7% in pre-TDM and 42.7% in the TDM group
  • The authors did not identify a significantly higher rate of anti-TNF cessation in either group
  • Only 12% of patients in their practice were receiving combination therapy

In the discussion, the authors review three pivotal studies which also support proactive TDM: TAXIT, TAILORIX, and PAILOT.

My take: While this was an observational study with historical controls, the findings are convincing that proactive TDM is helpful, particularly in patients who are not receiving combination therapy.

Related blog posts:

March 31, 2021

Adjustment of azathioprine dose in NUDT15 intermediate metabolizers, COVID-19 in Georgia & COVID-19 Phase 1 Vaccine Study

LA Jackson et al. NEJM 2020; DOI: 10.1056/NEJMoa2022483. Link:  An mRNA Vaccine against SARS-CoV-2 — Preliminary Report  The mRNA-1273 vaccine induced anti–SARS-CoV-2 immune responses in all participants (n=45), and no trial-limiting safety concerns were identified.

______________________________________________________________________

COVID-19 in Georgia (Data from 7/13/20):


B Kang et al. AP&T 2020; https://doi.org/10.1111/apt.15810. Thanks to Ben Gold for this reference. Full text: Adjustment of azathioprine dose should be based on a lower 6‐TGN target level to avoid leucopenia in NUDT15 intermediate metabolizers

Background: “In addition to TPMT polymorphisms, a recent genome‐wide association study reported that a missense variant of nudix hydrolase 15 (NUDT15 ), which encodes a novel thiopurine‐metabolizing enzyme, was strongly associated with thiopurine‐induced leucopenia especially in Asians”

Key findings:

  • Among the 167 pediatric patients included, leucopenia was observed in 16% (19/119), 44% (20/45) and 100% (3/3) of the NUDT15 normal, intermediate and poor metabolizers respectively ( < 0.001)
  • There was a positive association between 6‐TGN levels and leucopenia among the NUDT15 intermediate/TPMT normal metabolizers
  • In order to reduce the development of thiopurine‐induced leucopenia (<15%) in NUDT15 intermediate metabolizers, adjustment of azathioprine doses should be based on a lower 6‐TGN target level (<167.1 pmol/8 × 108 RBC)

Limitations: single-center, retrospective study and possible selection bias

My take: While 6-TGN levels between 235-400 are typically considered therapeutic, individuals with intermediate metabolism are at increased risk for leukopenia and may respond at lower levels.  This study indicates that careful dosing and close monitoring is needed for NUDT15 intermediate metabolizers

Related blog posts:

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

Expert Guidance on Inflammatory Bowel Disease (Part 2)

A recent issue of Clinical Gastroenterology and Hepatology focused solely on the clinical features and management of inflammatory bowel disease. Even for those with expertise in IBD, there is a lot of useful information and concise reviews of what is known.

Here are some of my notes from this issue (part 2)

S Danese et al. Clinical Gastroenterol Hepatol: 2020; 18: 1280-90. Positioning Therapies in Ulcerative Colitis

This is a good article but recent AGA publications are probably better –there are some links below. One statement that was interesting: “the safety profile of vedolizumab seems even better than placebo in terms of risk of serious” adverse events. The authors favored infliximab in combination with azathioprine in those needing biologic therapy with moderate-severe UC.

Related blog posts:

S Vermeire et al. Clinical Gastroenterol Hepatol: 2020; 18: 1291-9. How, When, and for Whom Should We Perform Therapeutic Drug Monitoring?

“Although reactive TDM, testing at time of loss of response, is widely accepted in practice, especially for anti–tumor necrosis factor antibodies, there are less data for the other monoclonal antibodies belonging to other classes. Besides reactive testing, there is a movement toward proactively adjusting biologic dosing to prevent loss of response, in keeping with the tight control philosophy of inflammatory bowel disease care.” The authors favor proactive monitoring: “we are now beginning to see with well-powered proactive TDM studies” that proactive monitoring can maximize the benefits of TDM with “the potential to maximize durability of biologics and improve the outcomes of IBD patients.”

Related blog posts:

PS Dulai et al. Clinical Gastroenterol Hepatol: 2020; 18: 1300-8. How Do We Treat Inflammatory Bowel Diseases to Aim For Endoscopic Remission?

The initial part of this article reviews treatment targets -resolution of symptoms and resolution of endoscopic damage. The algorithm provides the authors’ suggested approach:

  • At initiation of therapy, patients should have a full assessment.  In addition to ileocolonoscopy, for patients with CD, the authors recommend cross-sectional imaging.
  • After treatment initiation, the authors recommend biomarker assessment every 3 months.  Mucosal assessment can occur 6-9 months after treatment initiation.
  • For UC, the authors note that fecal calprotectin (FC) “appears to be more stratightforward, and a cutoff of 250 mcg/g can be used reliably across all scenarios to make treatment adjustments.”  Though, they recommend endoscopic confirmation prior to transition to a biologic or small molecule therapy.
  • For CD, the authors suggest making treatment adjustments in those with FC >250 mcg/g and in those with lower values, followup colonoscopy is recommended.
  • The authors note that in the post-operative setting with CD, mucosal inflammation precedes symptomatic activity and “waiting for symptoms to emerge may unnecessary allow for disease progression.”
  • The authors suggest that tighter disease control will reduce disease-related complications, while acknowledging a lack of prospective clinical trials.
  • One thorny issue: :”For CD: it remains unclear what degree of residual mucosal healing is acceptable to impact important outcomes such as CD-related complications, hospitalizations, and surgeries.”

Related blog posts:

M Allocca et al. Clinical Gastroenterol Hepatol: 2020; 18: 1309-23. Use of Cross-Sectional Imaging for Tight Monitoring of Inflammatory Bowel Diseases

“Computed tomography is limited by the use of radiation, while the use of magnetic resonance enterography (MRE) is limited by its cost and access. There is growing interest in bowel ultrasound that represents a cost-effective, noninvasive, and well-tolerated modality in clinical practice, but it is operator dependent… Diffusion-weighted imaging (DWI) is a MR imaging technique that increasingly is used in both IBD and non-IBD conditions and has been shown to be a valuable and accurate tool for assessing and monitoring IBD activity.

L Beaugerie et al. Clinical Gastroenterol Hepatol: 2020; 18: 1324-35. Predicting, Preventing, and Managing Treatment-Related Complications in Patients With Inflammatory Bowel Diseases

The first part of this article reviews potential adverse effects from the medications used for IBD treatment, noting in Table 1 that there are not complications to monitor for with both vedolizumab and ustekinumab.

The article reviews infections, vaccination strategies and issues related to malignancy Some of the recommendations:

  • vaccine against pneumococcus should be given before patients begin immunosuppressive therapy
  • physicians should consider giving patients live vaccines against herpes zoster (in adults) before they begin immunosuppressive therapy or a recombinant vaccine, when available, at any time point during treatment
  • sun protection and skin surveillance from the time of diagnosis are recommended
  • despite concerns about therapy, the authors note that “the extensive use of immunosuppressive therapy leads to a substantial decrease in the incidence of IBD complications, with a globally favorable benefit-risk ratio, which can be optimized further thanks to a good degree of awareness and knowledge of drug complications.”

It is interesting that this article (and the entire issue) does not address mental health concerns related to the diagnosis of IBD.  This likely creates more morbidity and complications than most of the other issues that are discussed.

Above: Why did the picture go to jail? Because it was framed.

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.

IBD Updates December 2019

SR Gupta et al. JPGN 2019; 69: 544-50.  This article reports on preliminary experience in 54 children who received external (non-hospital) infliximab infusions. The average age was 17.6 years. The authors noted no serious safety concerns.  Prior to arranging these infusions, the authors insisted on the following:

  • Infusion services had to guarantee pediatric trained nurses with PALS certification
  • Emergency medications had to be available
  • A plan for emergency communication was arranged
  • Postinfusion communication would occur with each infusion

BN Limketkai et al. Inflamm Bowel Dis 2019; 25: 1828-37.  This study, using Truven Health MarketScan database (2007-16) reviewed proactive or reactive mucosal monitoring after biologic initiation in IBD.  Early (< 6 months) proactive monitoring (88% endoscopy-based) was performed in 11% (n=2195/19,899) of patients with Crohn’s and 12.8% (925/7247) of patients with ulcerative colitis.

  • “Early proactive monitoring was associated with a reduction in disease-related complications for CD (aHR 0.90) and UC (aHR 0.87) and predominantly driven by a reduction in corticosteroid use.”
  • Another interesting finding was that ~40% of patients had biologic therapy initiated without assessment of mucosal disease activity within 6 months.
  • The authors state that disease monitoring is typically more useful in CD than UC because with the latter, cessation of bleeding and diarrhea appear to be adequate surrogates.
  • This study was not able to assess whether a biomarker like fecal calprotectin would be suitable due to its low utilization.

RZ Cohen, BT Schoen, S Kugathasan, CG Sauer. JPGN 2019; 69: 551-6. In this chart review, the authors identified anti-drug antibodies (ADA) in 24.8% (n=58) of patients undergoing therapeutic drug monitoring (n=234) with both infliximab and adalimumab.  54% of this group had antibody suppression with dose optimization. Of note, 37 patients had detectable ADA at time of initial drug monitoring. Dose optimization was 10 mg/kg every 4 weeks with infliximab or 40 mg weekly with adalimumab. Patients who were switched to a second anti-TNF agent (n=23) were not more likely to develop ADA to the second agent (small sample size). Also, the authors caution that in the five patients with ADA levels (>10 U/mL), dose optimization failed and patients required a therapeutic switch. My take: This study provides some useful information about the frequency of ADA.  My view is that the actual drug level is more critical than the presence of ADA; though, the presence of high ADA often precludes the ability to deliver a therapeutic drug level.

Related blog posts:

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.

CCFA: Updates in IBD Conference (part 1)

My notes from a recent Georgia Chapter of CCFA’s conference. There could be errors of omission, transcription and/or errors in context based on my understanding.

Adam Cheifetz, MD Harvard School of Medicine

Optimizing IBD Treatments

  • Earlier treatment with effective therapies
  • Utilizing therapeutic drug monitoring

Goals are clinical and endoscopic remission

  • Imaging if not visible on endoscopy
  • Biomarker remission -adjunctive goal
  • Symptoms and endoscopy do not have good correlation in Crohn’s disease
  • Endoscopic healing associated with better outcomes
  • Treatment –>assessment –> adjust treatment if goal is not met

Biologic Agents:

  • First agent works best; TNF-exposed patients do not respond as well as TNF-naive patients to subsequent biologic
  • High rate of secondary loss of response

Therapeutic Drug Monitoring:

  • Combination therapy in Sonic study was associated with higher infliximab levels. It appears that optimized monotherapy is as effective as combination therapy (Colombel study).
  • Fistula treatment requires higher biologic levels
  • Lower biologic drug levels associated with development of antidrug antibodies
  • Proactive monitoring –recommended
  • Both infliximab and adalimumab are frequently underdosed, especially in pediatrics –>another reason for proactive monitoring
  • If sicker patients, consider checking TDM at week 10; less sick patients, reasonable to consider TDM at week 14

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.

Combination Therapy Study Points to Central Role of Adequate Drug Levels

A recent study (JF Colombel et al. Clin Gastroenterol Hepatol 2019; 17: 1525-32) examines the effect of combination therapy and drug levels in achieving corticosteroid-free remission at week 26 (CSFR26).

The authors performed a post hoc analysis from 206 patients with Crohn’s disease (CD): 97 monotherapy with infliximab & 109 with combination infliximab/azathioprine

Key findings:

  • The proportions of patients achieving CSFR26 were not significantly greater among those receiving combination therapy vs monotherapy within the same serum infliximab concentrations
  • Mean trough infliximab concentrations in the combination therapy were higher than for monotherapy: 3.54 mcg/mL vs. 1.55 mcg/mL
  • Higher levels of antidrug antibodies were seen with monotherapy: 35.9% vs 8.3% of those with combination therapy.  Antidrug antibodies were detected only in those with lowest quartile of infliximab trough levels.

My take: This study indicates that combination therapy’s higher efficacy is due to  favorable pharmacokinetics rather than drug synergy.  If good infliximab trough levels can be achieved with infliximab monotherapy, this may obviate the need for combination therapy.  The uncertain factor is whether closer attention to trough levels will minimize the development of antidrug antibodies as effectively as the use of combination therapy.

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.

Sagrada Familia, Barcelona

IBD Update Feb 2019

Briefly noted:

B Feagan et al. Systematic review: efficacy and safety of switching patients between reference and biosimilar infliximab. Alim Pharm Ther 2019 Jan;49(1):31-40. “While available data have not identified significant risks associated with a single switch between reference and biosimilar infliximab, the studies available currently report on only single switches and were mostly observational studies lacking control arms. Additional data are needed to explore potential switching risks in various populations and scenarios.”

MP Pauly et al. Incidence of Hepatitis B Virus Reactivation and Hepatotoxicity in Patients Receiving Long-term Treatment with Tumor Necrosis Factor Antagonists. Clin Gastroenterol Hepatol 2018; 16: 1964-73. Using data from 8887 adults, this retrospective review found  “HBV reactivation iin 39% of patients who were HBsAg+ before therapy, but not in any patients who were HBsAg-negative and anti-HBc+ before therapy.”

D Lauritzen et al. Pediatric Inflammatory Bowel Diseases: Should We Be Looking for Kidney Abnormalities? Inflamm Bowel Dis 2018; 24: 2599-2605. In a cross-sectional cohort of 56 children with IBD, the authors found 25% “had either previously reported kidney disease or ultrasonographic signs of chronic kidney disease.” The authors note that plasma cystatin C is a useful biomarker for glomerular filtration as it less dependent on nutritional status; it is increased in the setteing of a decline in GFR.

L Pouillon et al. Mucosal Healing and Long-term Outcomes of Patients with Inflammatory Bowel Diseases Receiving Clinic-Based vs Trouhg Concentration-Based Dosing of Infliximab. Clin Gastroenterol Hepatol 2018; 16: 1276-83.  This retrospective study with patients who completed TAXIT maintenance phase found that patients who received trough-based infliximab dosing had a lower discontinuation rate of infliximab compared with clinic-based dosing (2 of 21 [10%]  vs. 10 of 27 [37%]).  However, both groups had >75% of patients able to continue infliximab for more than 3 years after the trial.

N Ouldali et al. Early Arthritis Is Associated With Failure of Immunosuppressive Drugs and Severe Pediatric Crohn’s Disease Evolution. Inflamm Bowel Dis 2018; 24: 2423-30. In this retrospective study with 272 patients with Crohn’s disease, 23.9% (n=65) developed arthritis and this was associated with failure of immunosuppressive drugs with OR of 6.9 after 2 years. In this study, immunosuppressive drugs refers to thiopurines and methotrexate.  By the completion of study, a much greater proportion of those with arthritis required biologic treatment (76% vs 32%, OR 4.3)

Vedolizumab Drug Levels –Are They Needed?

A recent retrospective study (E Dreesen et al Clin Gastroenterol Hepatol 2018; 16: 1937-46) with 179 consecutive patients (66 with ulcerative colitis, and 113 with Crohn’s disease) found that vedolizumab (VDZ) trough concentrations were correlated with response.

Key findings:

  • VDZ trough >30 mcg/mL at week 2, >24 mcg/mL at week 6, and >14 mcg/mL during maintenance were associated with effectiveness endpoints including endoscopic healing, physician global assessment and biochemical response (based on CRP).
  • Median VDZ trough levels during induction were 27.7 mcg/mL at week 2, 27.4 mcg/mL at week 6. With standard dosing, the maintenance VDZ trough was 13.5 mcg/mL at week 14
  • Higher BMI and more severe disease, based on CRP, albumin, and/or hemoglobin, were associated with lower VDZ trough levels and lower probability of mucosal healing (P<.05).

Interestingly, in the discussion the authors note that VDZ troughs above  3 mcg/mL completely saturate α4β7 intergrin.  This physiologic phenomenon is hard to reconcile with data showing better response with higher VDZ levels.  The authors note that “at present, there are not enough data in our study to support the role for TDM to guide clinical decision-making on dose escalation for vedolizumab.”

My take: This study implies that VDZ levels may help predict response but are not necessarily helpful in determining whether dose escalation is warranted.

Related blog posts:

Riverwalk, Chattanooga