Vedolizumab Exposure Levels and Clinical Outcomes in Ulcerative Colitis

Determining the Potential for Dose Optimisation

Mark T. Osterman; Maria Rosario; Karen Lasch; Morris Barocas; Jayson D. Wilbur; Nathanael L. Dirks; Marc R. Gastonguay

Disclosures

Aliment Pharmacol Ther. 2019;49(4):408-418. 

In This Article

Results

Vedolizumab Exposure-response Relationship and Proposed Potential Target Concentrations

Of the 746 patients who received at least one dose of vedolizumab in GEMINI 1, 693 (93%) had vedolizumab concentrations assessed at week 6 and were included in the exposure-response analysis. Characteristics of these patients are shown in Table 1. Of note, patients had a mean disease duration of 6.9 years, mean complete Mayo Score of 8.5 and a mean partial Mayo Score of 6.0; 347 (50%) had disease proximal to the splenic flexure, and 281 (41%) had received prior anti-TNFα therapy.

Trends were observed between patient-specific covariates and estimated clearance and concentrations of vedolizumab (Figure 1). Specifically, history of prior anti-TNFα treatment (P < 0.0001), lower serum albumin concentration (P < 0.0001) and higher faecal calprotectin concentration (P < 0.0001) were each associated with higher estimated vedolizumab clearance quartiles at week 6 and lower estimated vedolizumab concentration quartiles at both week 6 and steady state. Similar but less consistent associations were also observed for patient age (P ≤ 0.0210) and weight (P ≤ 0.0013). These findings indicated a strong imbalance in the distribution of measured covariates across exposure or clearance quartiles, but it is unknown if similar imbalance existed across other unmeasured factors. For each vedolizumab concentration quartile at week 6 and steady state prior to covariate-based case-matching, the majority of the ASDMs for the patient-specific covariate main effects were >0.1. However, these ASDMs were <0.1 after case-matching, indicating good matching between patients receiving vedolizumab and those receiving placebo.

Figure 1.

Patient-specific covariates (A) weight, (B) age, (C) prior anti-TNFα therapy, (D) serum albumin and (E) faecal calprotectin, stratified by quartiles from low (quartile 1) to high (quartile 4) for estimated concentration and estimated clearance of vedolizumab at week 6 and at steady state. The relationship between patient-specific covariates and estimated vedolizumab clearance and vedolizumab concentrations was expressed as P values for the monotonic trend analysis (A, B, D, E). P values for prior anti-TNFα therapy were determined using the exact Cochran-Armitage trend test (C). TNFα, tumour necrosis factor alpha

Given the case-matching-adjusted data, rates of clinical response and remission decreased with increasing estimated vedolizumab clearance quartiles at week 6, whereas these rates rose with increasing estimated vedolizumab concentration quartiles at both week 6 and steady state (P < 0.0001; Figure 2). Specifically, clinical response rates ranged from 27%-32% in the highest clearance/lowest vedolizumab concentration quartiles to 62%-66% in the lowest clearance/highest vedolizumab concentration quartiles. Clinical remission rates ranged from 6%-8% in the highest clearance/lowest vedolizumab concentration quartiles to 33%-36% in the lowest clearance/highest vedolizumab concentration quartiles. When examining the distribution of the odds ratios of clinical response and remission by estimated vedolizumab clearance quartiles at week 6 and by estimated vedolizumab concentration quartiles at week 6 and steady state, consistent trends towards increasing odds ratios with decreasing clearance/increasing vedolizumab concentration quartiles were observed. These trends were most apparent for clinical response with week 6 vedolizumab clearance and steady-state vedolizumab concentrations, and for clinical remission with week 6 vedolizumab concentrations (Figure 3).

Figure 2.

Clinical response (A) and remission (B) (adjusted for age, weight, history of prior anti-TNFα therapy, serum albumin concentration and faecal calprotectin concentration), stratified by quartiles from low (quartile 1) to high (quartile 4) for estimated concentration and estimated clearance of vedolizumab at week 6 and steady state (n = 170–177). P values were determined using the exact Cochran-Armitage trend test. Clinical response was defined as a reduction in partial Mayo Score of ≥3 points and a ≥30% decrease from baseline, with a decrease of ≥1 point on the rectal bleeding sub-score or an absolute rectal bleeding score ≤1. Clinical remission was defined as a partial Mayo Score of ≤2 points with no individual sub-score >1 point and mucosal healing (endoscopic sub-score ≤1). TNFα, tumour necrosis factor alpha

Figure 3.

Odds ratios for: (A) clinical response and remission by estimated vedolizumab clearance quartiles at week 6; (B) vedolizumab concentration quartiles at week 6; and (C) estimated vedolizumab trough concentration quartiles at steady state from low (quartile 1) to high (quartile 4). Dashed lines indicate zero

Because an estimated vedolizumab clearance of <0.14 L/d was associated with high rates of clinical response, potential target vedolizumab concentrations at the clinically important time points of week 6 (during induction), week 14 (end of induction period) and steady state (representing trough, during maintenance) were proposed based on this value. Using the vedolizumab pharmacokinetic model and the standard FDA-approved every-8-weeks maintenance dosing schedule of vedolizumab, the following concentrations were calculated for a clearance of ≤0.14 L/d: >37.1 μg/mL at week 6, >18.4 μg/mL at week 14 and >12.7 μg/mL at steady-state trough.

Association of early vedolizumab concentrations and clinical remission at weeks 14 and 52

To determine the earliest time point at which measurement of vedolizumab concentrations was associated with clinical remission at week 14, vedolizumab concentration data at weeks 2, 4 and 6 were assessed in patients randomised to vedolizumab 300 mg every 8 weeks in the maintenance arm of GEMINI 1. Patients in this arm were similar to those receiving vedolizumab 300 mg every 4 weeks or to those receiving placebo in terms of baseline characteristics (including disease activity and prior immunomodulator use), except for a numerically longer disease duration for patients receiving vedolizumab every 4 weeks (disease duration of 7.6 years) compared with vedolizumab every 8 weeks (disease duration of 6.2 years) (Table S1). Patients who achieved clinical remission at week 14 showed higher week 4 (P = 0.0328) and week 6 (P = 0.0418) vedolizumab concentrations compared with those who did not achieve remission at week 14; at week 2, vedolizumab concentrations were generally similar between patients who later achieved remission at week 14 and those who did not (P = 0.4592; Figure 4). When examining clinical remission status at week 14 by vedolizumab concentration quartiles at weeks 2, 4 and 6, a consistent trend for increasing remission with increasing vedolizumab concentration was observed at week 4 (P = 0.0469) and week 6 (P = 0.0098), but not at week 2 (P = 0.6766; Figure 5). At week 6, a 40% remission rate was reported in the lowest concentration quartile vs 74% in the highest quartile.

Figure 4.

Vedolizumab concentrations at weeks 2, 4 and 6, stratified by remission status at week 14.a Pvalues were determined using the Wilcoxon rank-sum test. aPatients positive for human anti-human antibodies were excluded from this analysis; patients received vedolizumab at weeks 0, 2, 6 and 14; clinical remission was defined as a partial Mayo Score of ≤2 points with no individual sub-score >1 point. Patients were not case-matched for this analysis. Midlines represent medians, and individual points inside the boxes represent means. Box limits represent 25th and 75th percentiles. Whiskers (error bars) represent highest and lowest points within 1.5× interquartile range. Individual points above and below whiskers represent outliers

Figure 5.

Clinical remission statusa at week 14 in patients with ulcerative colitis, stratified by estimated vedolizumab concentration quartiles from low (quartile 1) to high (quartile 4) at weeks 2, 4 and 6. P values were determined using the exact Cochran-Armitage trend test. aClinical remission was defined as a partial Mayo Score of ≤2 points with no individual sub-score >1 point. Patients were not case-matched for this analysis

Given that it was only at week 6 that vedolizumab concentrations exhibited a consistent association with rates of clinical remission at week 14, the association between clinical remission at week 52 and early vedolizumab concentrations was restricted to week 6, but was expanded to include the entire GEMINI 1 cohort. Clinical remission rates at week 52 increased consistently with increasing quartiles of vedolizumab concentration at week 6, with a 15% remission rate in the lowest concentration quartile and 37% in the highest quartile (Figure 6).

Figure 6.

Clinical remissiona rates at week 52 in patients with ulcerative colitis, stratified by estimated vedolizumab concentration quartiles from low (quartile 1) to high (quartile 4) at week 6. Pvalues were determined using the exact Cochran-Armitage trend test. aClinical remission was defined as a partial Mayo Score of ≤2 points with no individual sub-score >1 point. Patients were not case-matched for this analysis

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