Post-Induction High Adalimumab Drug Levels Predict Biological Remission at Week 24 in Patients With Crohn's Disease

Abstract Background Anti-tumor necrosis factor-α (anti-TNFa) therapy have been established as an effective maintenance treatment for complicated Crohn’s Disease (CD). However, the efficacy of Infliximab (IFX) and Adalimumab (ADM) may be affected by low serum levels and/or the presence of anti-drug antibodies (ADA). This reinforces the importance of therapeutic drug monitoring (TDM). We aim to assess the clinical benefit of proactive vs. reactive TDM. Secondly, to assess the impact of TDM on clinical management. Thirdly, to identify risk factors for low serum drug levels and the development of ADA in CD patients. Methods This was a single-centred observational cohort study performed at a tertiary hospital, comprising of total 229 CD patients: 142 received IFX and 87 received ADM, who have had a trough drug level, tested using enzyme-linked immunosorbent assay. Demographic and clinical data were retrospectively collected from electronic medical records. Fisher’s Exact Test was used to determine if there are nonrandom associations between variables. A p-value of less than 0.05 was considered statistically significant. Results One hundred and fourteen patients (49%) receiving a standard anti-TNFa regimen had subtherapeutic drug levels (67 had IFX < 3 μg/ml and 47 had ADM < 5 μg/ml). Interestingly, almost half of this cohort were asymptomatic. Reactive TDM completed among symptomatic patients have shown to have a statistically significant benefit in detecting subtherapeutic drug level (p = 0.0001). Following these results, only fifty-two patients (46%) had a change of therapy (29 IFX, 25 ADM); while the remaining sixty-two patients (54%) continued the same dosing regimen with only one documented admission within 90-days following the drug level being taken. Eight patients (4%) were found to have positive ADA, all in the presence of subtherapeutic drug levels. Two of these had a subsequent flare of their disease. They were all switched to another class of biologic therapy. Non-smoking status at diagnosis and the concomitant use of immunomodulator were found to have statistically significant associations with a therapeutic drug level (p = 0.0176 and p = 0.0001, respectively). Similarly, both of these risk factors were associated with lower risk of ADA formation (p = 0.0057 and p = 0.0165, respectively). Conclusion This study suggests that a large proportion of patients have subtherapeutic drug levels at standard dosing schedules. However, low drug levels do not correlate with a higher risk of complications if patients are in clinical remission. The results of this study also indicate that non-smoking status at diagnosis and the concomitant use of immunomodulator are associated with higher serum drug levels and lower risk of developing anti-drug antibodies.

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A101 USTEKINUMAB LEVELS MEASURED DURING INDUCTION ARE ASSOCIATED WITH CLINICAL AND BIOCHEMICAL OUTCOMES AT WEEK 12 OF TREATMENT IN CROHN’S DISEASE

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwz047.100 ◽

2020 ◽

Vol 3 (Supplement_1) ◽

pp. 117-118

Author(s):

M Walshe ◽

K Borowski ◽

K Boland ◽

S Rho ◽

J Stempak ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Negative Correlation ◽

Pearson Correlation ◽

Significant Negative Correlation ◽

Therapeutic Drug ◽

Tertiary Referral Centre ◽

Faecal Calprotectin ◽

Drug Levels ◽

Induction Dose

Abstract Background Therapeutic drug monitoring (TDM) helps guide use of anti-TNF drugs in IBD patients. In addition, higher anti-TNF levels during induction therapy have been shown to be associated with better clinical and endoscopic outcomes. The role of TDM for more novel biologics such as ustekinumab (an anti- IL-12/23 antibody used to treat Crohn’s disease) remains to be elucidated. Aims We set out to investigate correlations between ustekinumab drug levels measured during induction with clinical and biochemical outcomes in patients with Crohn’s disease. Methods Patients with Crohn’s disease commencing treatment with ustekinumab were recruited from a single tertiary referral centre. Standard weight-based induction dosing was used. TDM was performed at week 2 and week 6 following IV induction dose. A drug-tolerant assay (Prometheus) was used. Kruskal-Wallis test was used to examine association between induction dose and ustekinumab levels. CDAI, CRP, and faecal calprotectin (FCP) were measured at week 12. Pearson correlation co-efficient was used to assess the relationship between ustekinumab levels and i)CDAI ii)CRP and iii)FCP at week 12. Results A total of 38 ustekinumab levels in 21 patients were measured. Week 2 ustekinumab levels were available for 17 patients, 16 (94.1%) of whom had levels of greater or equal to 25μg/mL. (1 patient had a level of 19.5μg/mL.) Week 6 ustekinumab levels were available for 21 patients; median 15μg/mL (IQR 9.9–21.3). No patients had detectable antibodies to ustekinumab. There was no significant association between absolute induction dose and week 6 ustekinumab levels; p=0.46. Of the 21 patients with week 6 levels, CDAI, CRP and FCP were available for 18, 18 and 16 patients respectively; Median CDAI 103(IQR 42–249), median CRP 2.3mg/L(IQR 1.0–11.3), median FCP 269μg/g(IQR109-932). There was a significant negative correlation between week 6 ustekinumab levels and CDAI; r=-.609, p=0.007. A negative correlation between week 6 ustekinumab levels and FCP was also significant; r=-.526, p=0.037. There was no significant correlation between week 6 ustekinumab levels and CRP; r=-.259, p=0.298. Conclusions We have demonstrated inter-patient variation in drug pharmacokinetics at week 6 following induction dose of ustekinumab in patients with Crohn’s disease. Drug levels at week 6 are significantly associated with clinical and biochemical markers of disease activity (CDAI, faecal calprotectin) at week 12. Measurement of week 6 ustekinumab levels may aid early identification of patients at risk of primary non-response to ustekinumab. Funding Agencies Testing provided by Prometheus

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Sa1951 Intrapatient Variability in Adalimumab Drug Levels Within and Across Cycles in Crohn's disease

Gastroenterology ◽

10.1016/s0016-5085(16)31439-1 ◽

2016 ◽

Vol 150 (4) ◽

pp. S414 ◽

Cited By ~ 1

Author(s):

Mark G. Ward ◽

Lauren Beswick ◽

Phoebe Thwaites ◽

Julie Hogg ◽

Gennaro Rosella ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Drug Levels ◽

Intrapatient Variability

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Ustekinumab Drug Levels in Maternal and Cord Blood in a Woman With Crohn’s Disease Treated Until 33 Weeks of Gestation

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjx141 ◽

2017 ◽

Vol 12 (3) ◽

pp. 376-378 ◽

Cited By ~ 20

Author(s):

Catherine R Rowan ◽

Garret Cullen ◽

Hugh E Mulcahy ◽

Denise Keegan ◽

Kathryn Byrne ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Cord Blood ◽

Drug Levels

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Association of polymorphisms in C1orf106, IL1RN, and IL10 with post-induction infliximab trough level in Crohn’s disease patients

Gastroenterology Report ◽

10.1093/gastro/goz056 ◽

2019 ◽

Vol 8 (5) ◽

pp. 367-373

Author(s):

Jian Tang ◽

Cai-Bin Zhang ◽

Kun-Sheng Lyu ◽

Zhong-Ming Jin ◽

Shao-Xing Guan ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Prediction Model ◽

Regression Model ◽

Trough Level ◽

Single Gene ◽

Training Dataset ◽

Multivariate Logistic Regression Model ◽

Post Induction ◽

Multivariate Prediction

Abstract Background Trough levels of the post-induction serum infliximab (IFX) are associated with short-term and long-term responses of Crohn’s disease patients to IFX, but the inter-individual differences are large. We aimed to elucidate whether single gene polymorphisms (SNPs) within FCGR3A, ATG16L1, C1orf106, OSM, OSMR, NF-κB1, IL1RN, and IL10 partially account for these differences and employed a multivariate regression model to predict patients’ post-induction IFX levels. Methods The retrospective study included 189 Crohn’s disease patients undergoing IFX therapy. Post-induction IFX levels were measured and 41 tag SNPs within eight genes were genotyped. Associations between SNPs and IFX levels were analysed. Then, a multivariate logistic-regression model was developed to predict whether the patients’ IFX levels achieved the threshold of therapy (3 μg/mL). Results Six SNPs (rs7587051, rs143063741, rs442905, rs59457695, rs3213448, and rs3021094) were significantly associated with the post-induction IFX trough level (P = 0.015, P < 0.001, P = 0.046, P = 0.022, P = 0.011, P = 0.013, respectively). A multivariate prediction model of the IFX level was established by baseline albumin (P = 0.002), rs442905 (P = 0.025), rs59457695 (P = 0.049), rs3213448 (P = 0.056), and rs3021094 (P = 0.047). The area under the receiver operating characteristic curve (AUROC) of this prediction model in a representative training dataset was 0.758. This result was verified in a representative testing dataset, with an AUROC of 0.733. Conclusions Polymorphisms in C1orf106, IL1RN, and IL10 play an important role in the variability of IFX post-induction levels, as indicated in this multivariate prediction model of IFX levels with fair performance.

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Levels of Biosimilar Infliximab during and after Induction Treatment in Crohn’s Disease and Ulcerative Colitis—A Prospective Polish Population Study

Journal of Clinical Medicine ◽

10.3390/jcm10225311 ◽

2021 ◽

Vol 10 (22) ◽

pp. 5311

Author(s):

Anna Pękala ◽

Rafał Filip

Keyword(s):

Ulcerative Colitis ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Response To Therapy ◽

Response To Treatment ◽

Induction Treatment ◽

Therapeutic Drug ◽

Induction Phase ◽

Drug Levels ◽

Trough Levels

Background: Primary lack or secondary loss of response to therapy with infliximab is a significant problem. This study aimed to evaluate the response to treatment in patients with Crohn’s disease (CD) and ulcerative colitis (UC) achieving therapeutic and sub-therapeutic trough levels of biosimilar infliximab (CT-P13). Results: A total of 65 patients (32 with CD and 33 with UC) were recruited. The overall response rate in both CD and UC patients exceeded 80%. There were no significant differences in treatment response and CT-P13 levels for patients with CD or UC. We did not find significant differences in the percentage of patients achieving drug levels of 3 μg/mL at week 6, 10, or 12; a significant decrease was observed at week 14. Up to 55.5% of patients with CD and 64.3% of patients with UC with sub-therapeutic CT-P13 levels at week 14 primarily responded to treatment. Conclusions: Intermediate measurements of drug levels at weeks 10 and 12 did not capture any pronounced decrease in infliximab concentrations below therapeutic levels in either group, thus suggesting no clinical usefulness. A significant percentage of patients primarily responded to treatment despite sub-therapeutic drug levels after the induction phase.

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Augmented ustekinumab dosing is needed to achieve clinical response in patients with anti-TNF refractory pediatric Crohn’s disease: a retrospective chart review

F1000Research ◽

10.12688/f1000research.22673.2 ◽

2021 ◽

Vol 9 ◽

pp. 316

Author(s):

Phinga Do ◽

John Andersen ◽

Ashish Patel ◽

Gaith Semrin ◽

Luis Sifuentes-Dominguez ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Clinical Response ◽

Chart Review ◽

Pediatric Patients ◽

Retrospective Chart Review ◽

Previous Treatment ◽

Therapeutic Drug ◽

Duration Of Treatment ◽

Drug Levels

Background: Ustekinumab is a monoclonal antibody that inhibits interleukins 12 and 23. It is approved for treatment of Crohn’s disease (CD) in adults; however, there is a paucity of data regarding its use in pediatric CD. We describe our experience using ustekinumab in anti-TNF refractory CD pediatric patients. Methods: We performed a retrospective chart review on pediatric patients with CD who were started on ustekinumab from January 2016 to November 2018. We collected patient’s clinical history, previous treatment history, surgeries related to CD, disease severity, as measured by abbrPCDAI, and endoscopic severity as recorded by SES-CD before and after ustekinumab. Results: We identified 10 patients with CD who were started on ustekinumab due to non-response to currently approved agents. Seven patients needed augmented maintenance dosing every 4-6 weeks to achieve clinical response or remission. Six of these seven patients had therapeutic drug monitoring during the course of treatment, with five patients showing subtherapeutic drug levels of <4.5 μg/mL while on standard maintenance dosing every 8 weeks, and four patients showing therapeutic drug levels of >4.5 μg/mL on augmented dosing interval. The remaining three patients were on standard maintenance dosing for the duration of treatment. Conclusion: In this retrospective chart review, 7 out of 10 patients with anti-TNF refractory pediatric-onset CD required augmented maintenance doses of ustekinumab to achieve clinical response or remission. A prospective study is needed to define appropriate ustekinumab dosing and interval in management of pediatric CD.

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