Abstract
BACKGROUND
Ulcerative colitis (UC) is a chronic inflammatory condition requiring continuous treatment and monitoring. There is limited pharmacokinetic data on vedolizumab during maintenance therapy and the effect of thiopurines on vedolizumab trough concentrations is unknown.
AIM
To investigate the exposure-response relationship of vedolizumab and the impact of thiopurine withdrawal in UC patients who have achieved sustained clinical and endoscopic remission during maintenance therapy.
METHODS
This is a post-hoc analysis of prospective randomized clinical trial (VIEWS) involving UC patients across 8 centers in Australia from 2018 to 2022. Patients in clinical and endoscopic remission were randomized to continue or withdraw thiopurine while receiving vedolizumab. We evaluated vedolizumab serum trough concentrations, presence of anti-vedolizumab antibodies, and clinical outcomes over 48 weeks to assess exposure-response association and impact of thiopurine withdrawal.
RESULTS
There were 62 UC participants with mean age of 43.4 years and 42% were females. All participants received vedolizumab as maintenance therapy with 67.7% withdrew thiopurine. Vedolizumab serum trough concentrations remained stable over 48 weeks regardless of thiopurine use, with no anti-vedolizumab antibodies detected. Patients with clinical remission had higher trough concentrations at week 48. In quartile analysis, a threshold of > 11.3 μg/mL was associated with sustained clinical remission, showing a sensitivity of 82.4%, specificity of 60.0%, and an area of receiver operating characteristic of 0.71 (95%CI: 0.49-0.93). Patients discontinuing thiopurine required higher vedolizumab concentrations for achieving remission.
CONCLUSION
A positive exposure-response relationship between vedolizumab trough concentrations and UC outcomes suggests that monitoring drug levels may be beneficial. While thiopurine did not influence vedolizumab levels, its withdrawal may necessitate higher vedolizumab trough concentrations to maintain remission.
Keywords: Pharmacokinetic, Vedolizumab, Thiopurine, Ulcerative colitis, Trough concentration, Antibody, Inflammatory bowel diseases
Core Tip: This prospective study investigated the pharmacokinetic relationship between vedolizumab trough concentrations and clinical outcomes in ulcerative colitis patients who had achieved clinical remission, on vedolizumab with or without thiopurine. Vedolizumab levels remained stable over 48 weeks, regardless of thiopurine withdrawal. Significant associations between vedolizumab trough concentrations and endoscopic, histologic, and histo-endoscopic remission at week 48 suggest that monitoring vedolizumab levels could be beneficial, with a threshold of > 11.3 µg/mL linked to sustained clinical remission. Although thiopurine withdrawal did not affect vedolizumab levels, it may necessitate higher vedolizumab trough concentrations to maintain remission.
INTRODUCTION
Ulcerative colitis (UC) is a chronic inflammatory intestinal disease that results in a substantial burden on patients’ quality of life and to the healthcare system[1,2]. A significant proportion of patients suffer from moderate-to-severe disease activity necessitating treatment with an advanced therapy[3]. Long-term maintenance of biological therapy helps sustain clinical remission and prevent relapse. However, Immunogenic- and non-immunogenic causes of loss of response occur at a rate of 13% per year, sometimes requiring dose escalation or reduction in dose frequency of the biological agents. Optimization of these drugs through therapeutic drug monitoring has become a pivotal strategy that might sustain therapeutic efficacy[4,5]. This approach has demonstrated significant benefits, particularly evident with anti-tumor necrosis factor (TNF) therapy, where higher drug concentrations correlate with increased rates of remission[6,7]. Studies have also shown that thiopurine co-therapy is more effective than anti-TNF monotherapy in inducing clinical remission, primarily by reducing the formation of anti-drug antibodies[8,9].
Vedolizumab, an IgG monoclonal antibody with target binding of the α4β7 integrin on the surface of T-lymphocytes selectively inhibit the migration of lymphocytes into the gastrointestinal tract[10]. The exposure-efficacy relationship of vedolizumab in inflammatory bowel diseases (IBDs) is not well-defined. Post-hoc analyses of the GEMINI trial[11,12] and the recent ERELATE study[13] revealed a positive exposure-response relationship of vedolizumab. These studies suggested that vedolizumab concentration can serve as a predictor for both short- and long-term outcomes. In contrast, data from the ENTERPRET trial[14] and other observational studies[15,16] found no association between trough concentration and improved clinical outcomes. Furthermore, there is almost an absence of therapeutic drug monitoring data during the maintenance phase of UC treatment, and the potential impact of concomitant thiopurine therapy on vedolizumab trough concentrations in prospective studies. Our objective, therefore, was to prospectively evaluate the exposure-response relationship of vedolizumab on UC patients in clinical-endoscopic remission either with continuation of thiopurine-combination or after withdrawal of thiopurine but continuation of vedolizumab monotherapy.
MATERIALS AND METHODS
Patient population
We performed a prospective controlled trial on UC patients treated with vedolizumab that were randomized to either continue or to withdraw from thiopurine (VIEWS)[17]. Between 2018 to 2022, 8 IBD centers in Australia enrolled UC patients aged > 18 years treated with 300 mg intravenous vedolizumab every 8 weeks combined with an optimized thiopurine. All eligible participants were in corticosteroid-free clinical remission, with partial Mayo score < 2 without any subscore > 1 for at least 6 months, and in endoscopic improvement with Mayo endoscopic subscore 0-1. Participants at a ratio of 2:1 were randomized to either withdraw- or to continue their thiopurine whilst continuing vedolizumab. Every participant continued to receive eight weekly vedolizumab infusions with regular vedolizumab therapeutic drug monitoring, alongside eight weekly complete blood count, liver function test, serum C-reactive protein (CRP), electrolytes, urea, and creatinine. Fecal calprotectin and 6-thioguanine nucleotides (6-TGN) levels were measured at week 0 and 48. The study was approved by Sydney Local Health District Human Research Ethics Committee (HREC/17/CRGH/22) and Australian New Zealand Clinical trials registry (registration number ACTRN12618000812291). All participants provided written informed consent.
Vedolizumab serum trough concentration, anti-vedolizumab antibody and fecal calprotectin testing
Vedolizumab serum trough concentration and anti-vedolizumab antibody testing were performed at week 0, 24, and 48. Samples collected prior to vedolizumab infusions were centrifuged, stored at -70 °C and 5 μL of serum was batch tested by the Quest Pharmaceutical Services Holdings LLC (QPS, Newark, Delaware, United States) core laboratory. Enzyme-linked immunosorbent assay was performed in accordance with standard operating procedures and quality-controlled. Qualitative anti-vedolizumab antibodies, including neutralizing antibodies, were analyzed using electrochemiluminescence independent of drug concentrations. Fecal calprotectin levels were analyzed at Queensland Medical Laboratory Pathology (QML, Murarrie, Queensland, Australia) using the DiaSorin Liaison Calprotectin assay (DiaSorin, Saluggia, Italy).
Endpoints
The endpoints of interest of this post-hoc study were vedolizumab serum trough concentrations, antibodies to vedolizumab, their differences over time from week 0 to week 48, and between subjects on combination therapy with thiopurine and those on monotherapy. Clinical assessment was conducted every 8 weeks and measured by individual components of the partial Mayo clinical score as well as the composite score (range 0-9). Clinical remission was defined as partial Mayo score < 2 with no subscore exceeding 1, and the absence of corticosteroid-use. Biochemical remissions were determined through serum CRP level < 5 mg/L and fecal calprotectin concentration < 150 μg/g. Colonoscopy was performed at week 48 to assess endoscopic and histologic activity. Endoscopic improvement was defined as a Mayo endoscopic score of 0-1. Histologic remission was defined as a Nancy histological index of 0. Corticosteroid-free clinical remission was also evaluated at 2 years after study commencement.
Statistical analyses
Non-parametric continuous variables were presented as median and interquartile range and analyzed by the Mann-Whitney U test. Normally-distributed data were described by mean with standard deviation and analyzed by the t-test. Categorical variables were expressed as proportions and analyzed by χ2 test. A two-tailed P value of < 0.05 was deemed statistically significant. A Spearman correlation was performed to assess the association between vedolizumab serum trough concentrations and clinical outcomes at each measurement time point.
For longitudinal analysis, a mixed-effects logistic regression for repeated measures was utilized to investigate the association between remission rates and vedolizumab serum trough concentrations over time, assuming an unstructured covariance and adjusting interaction terms for concomitant thiopurine use, visit, interaction between outcome group and visit. Area of receiver operating characteristic (AUROC) curves were evaluated to identify optimal vedolizumab trough concentration with the maximal diagnostic yield. The analyses were performed using STATA version 17.0 (Stata Corporation, United States).
RESULTS
Patient characteristics and disease outcomes
In total, 62 UC (42% females, mean age 43.4 years) patients in clinical and endoscopic remission were prospectively recruited. Figure 1 illustrates the study enrollment process. Patients had typically failed corticosteroids and immunomodulators, and 22.6% had exposed to anti-TNF. Among the participants, 43 were previously on azathioprine 25-100 mg (69.3%), 16 (25.8%) on 6-mercaptopurine 12.5-100 mg, and 3 (4.8%) on thioguanine 20 mg. Two-thirds of the patients (n = 42) were randomized to withdraw thiopurines, including 27 previously on azathioprine, 13 on 6-mercaptopurine, and 2 on thioguanine. Table 1 provides the baseline characteristics and comparison between the thiopurine withdrawal and continuation groups. At week 0, the median 6-TGN levels were comparable between the withdrawal group and the continuation group, at 248 (186-326) vs 282 (186-367.5) pmol/8 × 108 red blood cell (RBC), respectively (P = 0.72). At 48 weeks, the median TGN level in the continuation group was 214 (163.5-358) pmol/8 × 108 RBCs, while levels were undetectable in the withdrawal group. A total of 82.3% of subjects remained in clinical remission, 79.6% in CRP biochemical remission, and 91.5% in fecal calprotectin biochemical remission. In addition, 68.4% of subjects were in endoscopic improvement and 58.2% were in histologic remission. Clinical relapse occurred in 11 patients (17.7%), with a median partial Mayo score of 4 and Mayo endoscopic score of 3. Two patients (10%) were in the continuation group and 9 patients (21.4%) were in the withdrawal group (P = 0.27). Corticosteroids were required in 5 patients in the withdrawal group, while no patients in the continuation group needed corticosteroids. The total corticosteroid-free clinical remission at 2 year was 77.4%.
Figure 1.
Study enrollment process. TGN: Thioguanine nucleotides.
Table 1.
Baseline characteristics and comparison between thiopurine withdrawal and continuation groups, n (%)/mean ± SD/ median (interquartile range)
|
|
Total (n = 62)
|
Withdrawal group (n = 42)
|
Continuation group (n = 20)
|
| Demographics | |||
| Female sex | 26 (41.9) | 21 (50) | 5 (25) |
| Age (years) | 43.4 ± 18.0 | 43.7 ± 19.0 | 42.8 ± 16.1 |
| Current/ex-smoker | 16 (25.8) | 11 (26.2) | 5 (25) |
| Disease extent | |||
| Left sided colitis | 41 (66.1) | 27 (64.3) | 14 (70) |
| Pancolitis | 21 (33.9) | 15 (35.7) | 6 (30) |
| Disease duration (years) | 7.5 (4-12) | 8 (3-13) | 6.5 (4-11.8) |
| Prior treatments | |||
| Corticosteroids | 57 (91.9) | 39 (92.9) | 18 (90) |
| Immunomodulators | 62 (100) | 42 (100) | 20 (100) |
| Anti-TNF | 14 (22.6) | 10 (23.8) | 4 (20) |
| Baseline assessment | |||
| Partial mayo score | 0 (0-0) | 0 (0-0) | 0 (0-0) |
| Mayo endoscopic score, 0-1 (n = 57) | 57 (100) | 42 (100) | 20 (100) |
| Histologic remission (n = 54) | 41 (75.9) | 25 (69.4) (n = 36) | 16 (88.9) (n = 18) |
| Laboratory values at baseline | |||
| Hemoglobin (g/L) | 139.6 ± 12.9 | 137.8 ± 13.8 | 143.2 ± 10.5 |
| Fecal calprotectin (µg/g) | 23.7 (7.9-65) | 17.7 (6.7-51.8) | 44.3 (10.5-124.6) |
| Albumin (g/L) | 41.4 ± 4.5 | 41.4 ± 5.0 | 41.2 ± 3.2 |
| CRP (mg/L) | 1.25 (0.5-3) | 1.3 (0.5-3.3) | 0.9 (0.2-2.5) |
| Vedolizumab serum trough concentrations | |||
| Week 0 (µg/mL) | 15.6 (10.8-20.8) | 16.2 (11.5-22.2) | 15.2 (10.3-16.9) |
| Week 24 (µg/mL) (n= 57) | 16.9 (12.0-22.1) | 17.8 (10.5-25.7) | 14.7 (12.2-19.7) |
| Week 48 (µg/mL) (n= 61) | 15.4 (11.3-21.7) | 15.9 (10.3-22.5) | 14.7 (12.4-18.4) |
| Outcomes at week 48 | |||
| Partial mayo score | 0 (0-0) | 0 (0-0) | 0 (0-0) |
| Clinical remission | 51 (82.3) | 33 (78.6) | 18 (90) |
| CRP (mg/L) | 1.2 (0-3.4) | 2.4 (0-6.4) (n = 32) | 1.2 (0-2.8) (n = 17) |
| CRP remission | 39 (79.6) | 24 (75) | 15 (88.2) |
| Fecal calprotectin (µg/g) | 15.4 (5.5-47.7) | 15.3 (5.5-43.2) (n = 31) | 17.5 (6.4-48.2) (n = 16) |
| Fecal calprotectin remission | 43 (91.5) | 27 (87.1) | 16 (100) |
| Endoscopic improvement (n = 57) | 39 (68.4) | 23 (62.6) (n = 37) | 16 (80) (n = 20) |
| Histologic remission (n = 55) | 32 (58.2) | 18 (48.7) (n = 37) | 14 (77.8) (n = 18) |
| Histo-endoscopic remission (n = 55) | 25 (45.5) | 12 (32.4) (n = 37) | 13 (72.2) (n = 18) |
| Clinical remission at 2 years | 48 (77.4) | 30 (71.4) | 18 (90) |
Anti-TNF: Anti-tumor necrosis factor; CRP: C-reactive protein.
Vedolizumab serum trough concentrations and anti-vedolizumab antibodies
In total, 180 serum samples were tested for vedolizumab serum trough concentrations and anti-vedolizumab antibodies at 3 time points. The median (interquartile range) vedolizumab serum trough concentrations were 15.6 μg/mL (10.8-20.8), 16.9 µg/mL (12.0-22.1), and 15.4 µg/mL (11.3-21.7) at week 0, 24, and 48, respectively. We observed significant positive correlations of vedolizumab serum trough concentrations at each measurement time point, with Spearman’s rho of 0.77 (P < 0.001) between week 0 and week 24, and 0.80 (P < 0.001) between week 0 and week 48. These findings suggest the stability of vedolizumab concentrations over the course of the study. Figure 2 shows distribution of vedolizumab serum trough concentrations at week 0 and 48. Irrespective of whether patients continued and withdrew thiopurine, there was no discernible difference in vedolizumab concentrations between the two groups. No patients tested positive for anti-vedolizumab antibodies throughout the study.
Figure 2.
Histograms demonstrates the distribution of vedolizumab serum trough concentrations. A: At week 0; B: At week 48; C: Scatter plot illustrates the relationship between vedolizumab serum trough concentrations at week 0 and week 48, categorized by thiopurine use.
Association between vedolizumab serum trough concentrations and treatment endpoints
We analyzed the association between vedolizumab serum trough concentrations against UC treatment endpoints. The median vedolizumab serum trough concentrations at week 48 was statistically significantly higher in patients who achieved clinical remission vs those that did not (P = 0.04, Figure 3). At week 0, higher vedolizumab serum trough levels were observed in the clinical remission group compared to the non-remission group, but without statistical significance (P = 0.47). No significant associations were found between trough levels at week 0 and CRP (P = 0.96), fecal calprotectin (P = 0.32), endoscopic improvement (P = 0.69), histologic (P = 0.44), and histo-endoscopic remission (P = 0.68) at week 48 (Table 2). Similarly, trough levels at week 48 did not show significant associations with CRP (P = 0.08), fecal calprotectin (P = 0.14), endoscopic improvement (P = 0.09), histologic (P = 0.78), and histo-endoscopic remission (P = 0.27) at the same time point. Histologic remission at baseline was significantly associated with higher vedolizumab serum trough levels at week 48 (P < 0.01). Patients achieving clinical remission after a 2-year follow-up showed higher vedolizumab serum trough concentrations at week 48 compared to those who did not (P = 0.02).
Figure 3.
Association of vedolizumab serum trough concentrations (µg/mL) with clinical remission. A: Concentration at week 0 vs clinical remission at week 48; B: Concentration at week 48 vs clinical remission at week 48; C: Concentration at week 48 vs clinical remission at 2 years.
Table 2.
Associations between vedolizumab serum trough concentrations and variable treatment endpoints, median (interquartile range)
|
Median vedolizumab serum trough concentrations (µg/mL)
|
No clinical remission
|
Clinical remission
|
P value
|
No endoscopic improvement
|
Endoscopic improvement
|
P value
|
No histologic remission
|
Histologic remission
|
P value
|
| Week 01 | 14.0 (6.4-22.2) | 15.7 (11.5-20.1) | 0.47 | 13.9 (10.4-22.2) | 15.9 (11.5-20.1) | 0.69 | 16.0 (11.1-21.7) | 15.5 (11.2-19) | 0.44 |
| Week 48 | 9.2 (5.4-21.7) | 16.3 (12.5-22.4) | 0.04 | 12.3 (8.1-21.9) | 17.7 (13.5-21.1) | 0.09 | 15.4 (9.8-21.9) | 17 (12.6-21.0) | 0.78 |
| 2 years2 | 12.4 (7.0-15.0) |
17.7 (12.6-22.5) |
0.02 |
Vedolizumab serum trough concentrations at week 0 vs remission rates at week 48.
Vedolizumab serum trough concentrations at week 48 vs clinical remission at 2 years.
The longitudinal analysis was performed through mixed model regressions, incorporating interaction terms to assess the association between vedolizumab serum trough concentrations and various clinical outcomes over specified time intervals. A trend towards significant association between vedolizumab serum trough concentrations and clinical remission at week 48 was observed (P = 0.10). Notably, the trough concentrations interaction with time had significant influence on endoscopic improvement (P = 0.02), histologic remission (P = 0.04), and histo-endoscopic remission (P = 0.02) (Figure 4). No association was observed for CRP (P = 0.37) and fecal calprotectin (P = 0.57) remission.
Figure 4.
Longitudinal association between vedolizumab serum trough concentrations at 3 distinct time points. A: Clinical; B: Endoscopy; C: Histology; D: Histo-endoscopic outcomes over 48 weeks.
Vedolizumab serum trough concentrations quartile and threshold analysis
We analyzed vedolizumab serum trough concentrations by quartiles to assess whether a threshold level correlated with outcomes (Table 3). In subjects with vedolizumab serum trough concentrations corresponding to quartile 2, there was a higher likelihood of achieving clinical, endoscopic, and histologic remission at week 48 compared to quartile 1. In subjects continuing thiopurine compared to those who withdrew thiopurine, there was a trend suggesting that lower vedolizumab serum trough levels were sufficient to achieve remission (Figure 5). Week 0 vedolizumab serum trough level > 11.5 μg/mL was associated with clinical remission at week 48 with a sensitivity of 76.5%, specificity of 45.5%, and an AUROC of 0.57 (95%CI: 0.35-0.79). Week 48 vedolizumab serum trough level > 11.3 µg/mL was associated with clinical remission with sensitivity of 82.4%, specificity of 60.0%, and an AUROC of 0.71 (95%CI: 0.49-0.93).
Table 3.
Quartile analysis of vedolizumab serum trough concentrations and variable outcomes at week 48, n (%)
|
Quartile at week 0
|
Vedolizumab trough concentrations
(µg/mL) |
Clinical remission
|
CRP remission
|
Fecal calprotectin remission
|
Endoscopic improvement
|
Histologic remission
|
Histo-endoscopic remission (%)
|
| 1 | 5.19-10.75 | 11 (73.3) | 8 (80.0) | 8 (80.0) | 8 (61.5) | 7 (58.3) | 6 (50.0) |
| 2 | 10.75-15.60 | 14 (87.5) | 12 (85.7) | 13 (92.9) | 10 (66.7) | 10 (66.7) | 7 (46.7) |
| 3 | 15.60-20.85 | 14 (87.5) | 9 (69.2) | 12 (100) | 12 (80.0) | 9 (60.0) | 7 (46.7) |
| 4 | 20.85-41.50 | 12 (80.0) | 10 (83.3) | 10 (90.9) | 9 (64.3) | 6 (46.2) | 5 (38.5) |
| Week 48 | |||||||
| 1 | 3.33-11.30 | 9 (60.0) | 5 (62.5) | 4 (57.1) | 4 (33.3) | 5 (45.5) | 3 (27.3) |
| 2 | 11.30-15.40 | 16 (94.1) | 12 (75.0) | 15 (100.0) | 14 (82.4) | 10 (62.5) | 7 (43.8) |
| 3 | 15.40-21.70 | 13 (86.7) | 10 (90.9) | 12 (100) | 12 (80.0) | 9 (60.0) | 8 (53.3) |
| 4 | 21.70-38.40 | 13 (86.7) | 12 (85.7) | 12 (92.3) | 9 (69.2) | 8 (61.5) | 7 (53.9) |
Figure 5.
Remission rates expressed per quartile. A: At week 0; B: At week 48.
DISCUSSION
In this prospective study, we investigated the association between vedolizumab serum trough concentrations and clinical endpoints while continuing vedolizumab as maintenance treatment with either continued or withdrew thiopurine. We observed a significant correlation of vedolizumab trough concentrations between three time points within 48 weeks. The continuation or withdrawal of thiopurine did not affect vedolizumab concentrations and no anti-vedolizumab antibodies were detected during the study. An exposure-response relationship was identified between trough concentrations at week 48 and clinical remission at both week 48 and 2 years. In longitudinal analysis, higher vedolizumab serum trough concentrations were associated with increased likelihood of endoscopic, histologic, and histo-endoscopic remission. A vedolizumab cut-off level of > 11.3 µg/mL showed highest diagnostic value for predicting long-term clinical remission during maintenance treatment. Patients who discontinued thiopurine may require higher vedolizumab trough concentrations to attain remission endpoints.
Several studies have investigated the association between vedolizumab serum trough concentrations during induction to early maintenance phase and clinical and endoscopic remission[12-15,18-23]. Most of these studies identified an exposure-efficacy relationship, underscoring the value of therapeutic drug monitoring. However, few studies have specifically addressed this association during long-term maintenance treatment[22,24-28]. A real-world study of 258 IBD patients, including 45% with UC treated with vedolizumab for median of 38 weeks, reported significantly higher vedolizumab concentrations in those achieving clinical, biochemical, or endoscopic remission[26]. However, the association in UC subgroup was marginally significant. Another retrospective study showed that histologic healing defined by Nancy index < 1 was associated with higher vedolizumab trough levels during maintenance treatment[25]. After 2.4 years of maintenance treatment with vedolizumab, the TUMMY study, which included 159 IBD patients (including 100 with UC) with 81% having prior exposure to anti-TNF, demonstrated an association between vedolizumab trough concentrations and biochemical, but not clinical remission[24]. A very low incidence of anti-vedolizumab antibodies was consistently found across all studies[22,29]. Discrepancies of pharmacokinetic findings among these studies can be due to various factors, including nature of the study, a mixed population of UC and CD, sample size, diverse measures of primary outcomes, varied duration of vedolizumab therapy, different intervals of vedolizumab infusion, prior exposure to anti-TNF, and distinct methodologies for measuring vedolizumab trough concentrations.
The median vedolizumab trough levels for favorable endpoints in UC have mainly been studied in induction phase. Reported values across studies range from 24.0 to 34.7 µg/mL[11,23,27]. A lower threshold for achieving remission was observed during the maintenance phase. A cohort study indicated vedolizumab concentrations in the range of 10.7-17 μg/mL during maintenance were associated with highest remission rates, recommending levels above 11.5 µg/mL for achieving corticosteroid-free clinical remission and biochemical remission[26]. Another recent study identified similar threshold of 11.9 μg/mL for clinical remission and a higher threshold of 15.3 µg/mL for objective remission at 1 year[22]. Consistent with these findings, our study found that the second quartile concentration (10.75-15.60 μg/mL) was associated with the highest rates of clinical and objective remission, suggesting a cut-off of > 11.3 μg/mL for predicting clinical remission during maintenance. While our findings suggest an exposure-response relationship for vedolizumab, this effect may reflect increased drug clearance during periods of disease activity. Interventional study is necessary to establish whether higher vedolizumab levels are indeed linked to improved outcomes.
Unlike anti-TNF therapy, the role of adding immunomodulator to vedolizumab in IBD patients remains controversial. Previous large retrospective analyses showed no discernible difference in clinical response or remission between combination therapy compared to vedolizumab monotherapy[30]. Similarly, a meta-analysis of 16 studies on vedolizumab found no clinical benefit associated with combination therapy during either induction or maintenance period, although these findings were limited by small participant numbers and retrospective study designs[31]. VIEWS study demonstrated that withdrawal of thiopurine in UC patients with remission may lead to increased biochemical, histological, and histo-endoscopic activity[17]. In this post-hoc analysis, we observed stable vedolizumab concentrations over 48 weeks regardless of thiopurine continuation or withdrawal. Outcomes remained consistent after adjusting thiopurine use in mixed-effects regression analysis. However, patients who discontinued thiopurine appeared to require higher vedolizumab levels to achieve remission, suggesting a potential pharmacokinetic interaction that favors the continuation of thiopurines in some patients. Additionally, patients with baseline histologic remission showed higher serum vedolizumab trough concentrations, suggesting that mucosal integrity may influence drug retention and subsequent clinical response, similarly to findings in infliximab studies[32,33].
Our study's prospective randomized controlled design allowed for comprehensive baseline characterization and complete data collection, including endoscopic and histologic assessments, which strengthened the reliability of the findings. Serial measurements of vedolizumab trough concentrations at three time points enabled a robust longitudinal analysis, reinforcing the observed associations. However, several limitations should be noted. The relatively small sample size may have limited the statistical power to detect smaller but clinically relevant differences, especially in post-hoc analyses. Additionally, the inclusion of anti-TNF exposed patients may have influenced responses to vedolizumab, and variability in treatment duration at initiation could have affected trough concentrations and clinical outcomes. While we explored the exposure-response relationship, causation remains uncertain, and the pharmacodynamic mechanisms of vedolizumab are not fully understood. These highlight the need for further research to confirm our findings in larger and more homogeneous populations.
CONCLUSION
Our study highlights the utility of vedolizumab trough concentrations for predicting outcomes in UC patients on combination therapy. Lower vedolizumab trough levels were associated with poorer outcomes, suggesting therapeutic drug monitoring might be clinically useful, particularly when treatment efficacy declines. Although vedolizumab serum trough concentrations remained consistent over time regardless of thiopurine continuation, withdrawing thiopurine may necessitate higher vedolizumab trough levels to achieve remission.
Footnotes
Institutional review board statement: The study was reviewed and approved by the Sydney Local Health District Human Research Ethics Committee (Approval No. HREC/17/CRGH/22).
Clinical trial registration statement: This study is registered at Australian New Zealand Clinical trials registry website (https://www.anzctr.org.au/). The registration identification number is ACTRN12618000812291.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
CONSORT 2010 statement: The authors have read the CONSORT 2010 statement, and the manuscript was prepared and revised according to the CONSORT 2010 statement.
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: Australia
Peer-review report’s classification
Scientific Quality: Grade B, Grade B, Grade C
Novelty: Grade C, Grade C, Grade C
Creativity or Innovation: Grade B, Grade B, Grade C
Scientific Significance: Grade B, Grade B, Grade B
P-Reviewer: Bayoumy AB; Yakut A S-Editor: Liu H L-Editor: A P-Editor: Wang WB
Contributor Information
Thanaboon Chaemsupaphan, Department of Gastroenterology and Liver Services, Concord Repatriation General Hospital, Sydney 2139, New South Wales, Australia; Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
Aviv Pudipeddi, Department of Gastroenterology and Liver Services, Concord Repatriation General Hospital, Sydney 2139, New South Wales, Australia; Faculty of Medicine and Health, University of Sydney, Sydney 2139, New South Wales, Australia.
Hui-Yu Lin, Department of Gastroenterology and Liver Services, Concord Repatriation General Hospital, Sydney 2139, New South Wales, Australia; Department of Gastroenterology, Tan Tock Seng Hospital, Singapore 308433, Singapore.
Sudarshan Paramsothy, Department of Gastroenterology and Liver Services, Concord Repatriation General Hospital, Sydney 2139, New South Wales, Australia; Faculty of Medicine and Health, University of Sydney, Sydney 2139, New South Wales, Australia; Faculty of Medicine and Health Sciences, Macquarie University, Sydney 2139, New South Wales, Australia.
Viraj C Kariyawasam, Department of Gastroenterology and Hepatology, Blacktown Hospital, Sydney 2148, New South Wales, Australia; Blacktown Clinical School, Western Sydney University, Sydney 2148, New South Wales, Australia.
Melissa Kermeen, Department of Gastroenterology and Liver Services, Concord Repatriation General Hospital, Sydney 2139, New South Wales, Australia.
Rupert W Leong, Department of Gastroenterology and Liver Services, Concord Repatriation General Hospital, Sydney 2139, New South Wales, Australia; Faculty of Medicine and Health, University of Sydney, Sydney 2139, New South Wales, Australia; Faculty of Medicine and Health Sciences, Macquarie University, Sydney 2139, New South Wales, Australia. rupert.leong@health.nsw.gov.au.
Data sharing statement
Data, analytic methods, and study materials are available to other researchers upon request to the corresponding author.
References
- 1.Gros B, Kaplan GG. Ulcerative Colitis in Adults: A Review. JAMA. 2023;330:951–965. doi: 10.1001/jama.2023.15389. [DOI] [PubMed] [Google Scholar]
- 2.Coward S, Clement F, Benchimol EI, Bernstein CN, Avina-Zubieta JA, Bitton A, Carroll MW, Hazlewood G, Jacobson K, Jelinski S, Deardon R, Jones JL, Kuenzig ME, Leddin D, McBrien KA, Murthy SK, Nguyen GC, Otley AR, Panaccione R, Rezaie A, Rosenfeld G, Peña-Sánchez JN, Singh H, Targownik LE, Kaplan GG. Past and Future Burden of Inflammatory Bowel Diseases Based on Modeling of Population-Based Data. Gastroenterology. 2019;156:1345–1353.e4. doi: 10.1053/j.gastro.2019.01.002. [DOI] [PubMed] [Google Scholar]
- 3.Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, Panaccione R, Ghosh S, Wu JCY, Chan FKL, Sung JJY, Kaplan GG. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017;390:2769–2778. doi: 10.1016/S0140-6736(17)32448-0. [DOI] [PubMed] [Google Scholar]
- 4.Cheifetz AS, Abreu MT, Afif W, Cross RK, Dubinsky MC, Loftus EV Jr, Osterman MT, Saroufim A, Siegel CA, Yarur AJ, Melmed GY, Papamichael K. A Comprehensive Literature Review and Expert Consensus Statement on Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease. Am J Gastroenterol. 2021;116:2014–2025. doi: 10.14309/ajg.0000000000001396. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Papamichael K, Cheifetz AS, Melmed GY, Irving PM, Vande Casteele N, Kozuch PL, Raffals LE, Baidoo L, Bressler B, Devlin SM, Jones J, Kaplan GG, Sparrow MP, Velayos FS, Ullman T, Siegel CA. Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. 2019;17:1655–1668.e3. doi: 10.1016/j.cgh.2019.03.037. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Vande Casteele N, Jeyarajah J, Jairath V, Feagan BG, Sandborn WJ. Infliximab Exposure-Response Relationship and Thresholds Associated With Endoscopic Healing in Patients With Ulcerative Colitis. Clin Gastroenterol Hepatol. 2019;17:1814–1821.e1. doi: 10.1016/j.cgh.2018.10.036. [DOI] [PubMed] [Google Scholar]
- 7.Syversen SW, Jørgensen KK, Goll GL, Brun MK, Sandanger Ø, Bjørlykke KH, Sexton J, Olsen IC, Gehin JE, Warren DJ, Klaasen RA, Noraberg G, Bruun TJ, Dotterud CK, Ljoså MKA, Haugen AJ, Njålla RJ, Zettel C, Ystrøm CM, Bragnes YH, Skorpe S, Thune T, Seeberg KA, Michelsen B, Blomgren IM, Strand EK, Mielnik P, Torp R, Mørk C, Kvien TK, Jahnsen J, Bolstad N, Haavardsholm EA. Effect of Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Therapy on Disease Control in Patients With Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial. JAMA. 2021;326:2375–2384. doi: 10.1001/jama.2021.21316. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, Lichtiger S, D'Haens G, Diamond RH, Broussard DL, Tang KL, van der Woude CJ, Rutgeerts P SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010;362:1383–1395. doi: 10.1056/NEJMoa0904492. [DOI] [PubMed] [Google Scholar]
- 9.Panaccione R, Ghosh S, Middleton S, Márquez JR, Scott BB, Flint L, van Hoogstraten HJ, Chen AC, Zheng H, Danese S, Rutgeerts P. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014;146:392–400.e3. doi: 10.1053/j.gastro.2013.10.052. [DOI] [PubMed] [Google Scholar]
- 10.Wyant T, Fedyk E, Abhyankar B. An Overview of the Mechanism of Action of the Monoclonal Antibody Vedolizumab. J Crohns Colitis. 2016;10:1437–1444. doi: 10.1093/ecco-jcc/jjw092. [DOI] [PubMed] [Google Scholar]
- 11.Rosario M, French JL, Dirks NL, Sankoh S, Parikh A, Yang H, Danese S, Colombel JF, Smyth M, Sandborn WJ, Feagan BG, Reinisch W, Sands BE, Sans M, Fox I. Exposure-efficacy Relationships for Vedolizumab Induction Therapy in Patients with Ulcerative Colitis or Crohn's Disease. J Crohns Colitis. 2017;11:921–929. doi: 10.1093/ecco-jcc/jjx021. [DOI] [PubMed] [Google Scholar]
- 12.Osterman MT, Rosario M, Lasch K, Barocas M, Wilbur JD, Dirks NL, Gastonguay MR. Vedolizumab exposure levels and clinical outcomes in ulcerative colitis: determining the potential for dose optimisation. Aliment Pharmacol Ther. 2019;49:408–418. doi: 10.1111/apt.15113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Vande Casteele N, Sandborn WJ, Feagan BG, Vermeire S, Dulai PS, Yarur A, Roblin X, Ben-Horin S, Dotan I, Osterman MT, Rosario M, Osborn TM, Panes J, Lindner D, Agboton C. Real-world multicentre observational study including population pharmacokinetic modelling to evaluate the exposure-response relationship of vedolizumab in inflammatory bowel disease: ERELATE Study. Aliment Pharmacol Ther. 2022;56:463–476. doi: 10.1111/apt.16937. [DOI] [PubMed] [Google Scholar]
- 14.Jairath V, Yarur A, Osterman MT, James A, Balma D, Mehrotra S, Yang L, Yajnik V, Qasim Khan RM. ENTERPRET: A Randomized Controlled Trial of Vedolizumab Dose Optimization in Patients With Ulcerative Colitis Who Have Early Nonresponse. Clin Gastroenterol Hepatol. 2024;22:1077–1086.e13. doi: 10.1016/j.cgh.2023.10.029. [DOI] [PubMed] [Google Scholar]
- 15.Hüttemann E, Muzalyova A, Gröhl K, Nagl S, Fleischmann C, Ebigbo A, Classen J, Wanzl J, Prinz F, Mayr P, Schnoy E. Efficacy and Safety of Vedolizumab in Patients with Inflammatory Bowel Disease in Association with Vedolizumab Drug Levels. J Clin Med. 2023;13 doi: 10.3390/jcm13010140. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Levartovsky A, Cohen I, Abitbol CM, Yavzori M, Fudim E, Picard O, Kopylov U, Ben-Horin S, Ungar B. Do Vedolizumab trough Levels Predict the Outcome of Subsequent Therapy in Inflammatory Bowel Disease? Biomedicines. 2023;11 doi: 10.3390/biomedicines11061553. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Pudipeddi A, Paramsothy S, Kariyawasam V, Paramsothy R, Ghaly S, Haifer C, An YK, Begun J, Connor SJ, Corte C, Ward MG, De Cruz P, Lan-San Fung C, Redmond D, Chan W, Mourad F, Kermeen M, Leong RW. Effects of Thiopurine Withdrawal on Vedolizumab-Treated Patients With Ulcerative Colitis: A Randomized Controlled Trial. Clin Gastroenterol Hepatol. 2024 doi: 10.1016/j.cgh.2024.04.019. [DOI] [PubMed] [Google Scholar]
- 18.Ungar B, Kopylov U, Yavzori M, Fudim E, Picard O, Lahat A, Coscas D, Waterman M, Haj-Natour O, Orbach-Zingboim N, Mao R, Chen M, Chowers Y, Eliakim R, Ben-Horin S. Association of Vedolizumab Level, Anti-Drug Antibodies, and α4β7 Occupancy With Response in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. 2018;16:697–705.e7. doi: 10.1016/j.cgh.2017.11.050. [DOI] [PubMed] [Google Scholar]
- 19.Schulze H, Esters P, Hartmann F, Stein J, Christ C, Zorn M, Dignass A. A prospective cohort study to assess the relevance of vedolizumab drug level monitoring in IBD patients. Scand J Gastroenterol. 2018;53:670–676. doi: 10.1080/00365521.2018.1452974. [DOI] [PubMed] [Google Scholar]
- 20.Hanžel J, Sever N, Ferkolj I, Štabuc B, Smrekar N, Kurent T, Koželj M, Novak G, Compernolle G, Tops S, Gils A, Drobne D. Early vedolizumab trough levels predict combined endoscopic and clinical remission in inflammatory bowel disease. United European Gastroenterol J. 2019;7:741–749. doi: 10.1177/2050640619840211. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Al-Bawardy B, Ramos GP, Willrich MAV, Jenkins SM, Park SH, Aniwan S, Schoenoff SA, Bruining DH, Papadakis KA, Raffals L, Tremaine WJ, Loftus EV. Vedolizumab Drug Level Correlation With Clinical Remission, Biomarker Normalization, and Mucosal Healing in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2019;25:580–586. doi: 10.1093/ibd/izy272. [DOI] [PubMed] [Google Scholar]
- 22.Steenholdt C, Lorentsen RD, Petersen PN, Widigson ES, Kloft C, Klaasen RA, Brynskov J. Therapeutic drug monitoring of vedolizumab therapy in inflammatory bowel disease. J Gastroenterol Hepatol. 2024;39:1088–1098. doi: 10.1111/jgh.16518. [DOI] [PubMed] [Google Scholar]
- 23.Yacoub W, Williet N, Pouillon L, Di-Bernado T, De Carvalho Bittencourt M, Nancey S, Lopez A, Paul S, Zallot C, Roblin X, Peyrin-Biroulet L. Early vedolizumab trough levels predict mucosal healing in inflammatory bowel disease: a multicentre prospective observational study. Aliment Pharmacol Ther. 2018;47:906–912. doi: 10.1111/apt.14548. [DOI] [PubMed] [Google Scholar]
- 24.Sivridaş M, Creemers RH, Wong DR, Boekema PJ, Römkens TEH, Gilissen LPL, van Bodegraven AA, Loeff FC, Rispens T, Derijks LJJ. Therapeutic Drug Monitoring of Vedolizumab in Inflammatory Bowel Disease Patients during Maintenance Treatment-TUMMY Study. Pharmaceutics. 2023;15 doi: 10.3390/pharmaceutics15030972. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Pouillon L, Rousseau H, Busby-Venner H, De Carvalho Bittencourt M, Choukour M, Gauchotte G, Zallot C, Danese S, Baumann C, Peyrin-Biroulet L. Vedolizumab Trough Levels and Histological Healing During Maintenance Therapy in Ulcerative Colitis. J Crohns Colitis. 2019;13:970–975. doi: 10.1093/ecco-jcc/jjz029. [DOI] [PubMed] [Google Scholar]
- 26.Ungaro RC, Yarur A, Jossen J, Phan BL, Chefitz E, Sehgal P, Kamal K, Bruss A, Beniwal-Patel P, Fox C, Patel A, Bahur B, Jain A, Stein D, Naik S, Dubinsky MC. Higher Trough Vedolizumab Concentrations During Maintenance Therapy are Associated With Corticosteroid-Free Remission in Inflammatory Bowel Disease. J Crohns Colitis. 2019;13:963–969. doi: 10.1093/ecco-jcc/jjz041. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Dreesen E, Verstockt B, Bian S, de Bruyn M, Compernolle G, Tops S, Noman M, Van Assche G, Ferrante M, Gils A, Vermeire S. Evidence to Support Monitoring of Vedolizumab Trough Concentrations in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. 2018;16:1937–1946.e8. doi: 10.1016/j.cgh.2018.04.040. [DOI] [PubMed] [Google Scholar]
- 28.Plevris N, Jenkinson PW, Chuah CS, Lyons M, Merchant LM, Pattenden RJ, Arnott ID, Jones GR, Lees CW. Association of trough vedolizumab levels with clinical, biological and endoscopic outcomes during maintenance therapy in inflammatory bowel disease. Frontline Gastroenterol. 2020;11:117–123. doi: 10.1136/flgastro-2019-101197. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Yarur AJ, Deepak P, Vande Casteele N, Battat R, Jain A, Okada L, Osterman M, Regueiro M. Association Between Vedolizumab Levels, Anti-vedolizumab Antibodies, and Endoscopic Healing Index in a Large Population of Patients with Inflammatory Bowel Diseases. Dig Dis Sci. 2021;66:3563–3569. doi: 10.1007/s10620-020-06669-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Hu A, Kotze PG, Burgevin A, Tan W, Jess A, Li PS, Kroeker K, Halloran B, Panaccione R, Peyrin-Biroulet L, Ma C, Ananthakrishnan AN. Combination Therapy Does Not Improve Rate of Clinical or Endoscopic Remission in Patients with Inflammatory Bowel Diseases Treated With Vedolizumab or Ustekinumab. Clin Gastroenterol Hepatol. 2021;19:1366–1376.e2. doi: 10.1016/j.cgh.2020.07.012. [DOI] [PubMed] [Google Scholar]
- 31.Yzet C, Diouf M, Singh S, Brazier F, Turpin J, Nguyen-Khac E, Meynier J, Fumery M. No Benefit of Concomitant Immunomodulator Therapy on Efficacy of Biologics That Are Not Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Diseases: A Meta-analysis. Clin Gastroenterol Hepatol. 2021;19:668–679.e8. doi: 10.1016/j.cgh.2020.06.071. [DOI] [PubMed] [Google Scholar]
- 32.Brandse JF, van den Brink GR, Wildenberg ME, van der Kleij D, Rispens T, Jansen JM, Mathôt RA, Ponsioen CY, Löwenberg M, D'Haens GR. Loss of Infliximab Into Feces Is Associated With Lack of Response to Therapy in Patients With Severe Ulcerative Colitis. Gastroenterology. 2015;149:350–5.e2. doi: 10.1053/j.gastro.2015.04.016. [DOI] [PubMed] [Google Scholar]
- 33.Goll R, Moe ØK, Johnsen KM, Meyer R, Friestad J, Gundersen MD, Kileng H, Johnsen K, Florholmen JR. Pharmacodynamic mechanisms behind a refractory state in inflammatory bowel disease. BMC Gastroenterol. 2022;22:464. doi: 10.1186/s12876-022-02559-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data, analytic methods, and study materials are available to other researchers upon request to the corresponding author.