O-003 Relationship Between Vedolizumab Pharmacokinetics and Endoscopic Outcomes of Patients With Ulcerative Colitis (2014)

A relationship between the pharmacokinetics (PK) of tumor necrosis factor antagonists and mucosal healing in patients with ulcerative colitis (UC) or Crohn’s disease was recently reported.1,2 This analysis examines the relationship between the PK of vedolizumab (VDZ), an α4β7 integrin antagonist, and endoscopic outcomes in patients with UC using population PK analysis. In GEMINI 1 (phase 3, randomized study), patients with UC received double-blind VDZ 300 mg or placebo (cohort 1) or open-label VDZ 300 mg (cohort 2) at weeks 0 and 2 during induction.3 Week 6 VDZ responders were rerandomized to placebo or VDZ 300 mg every 4 or 8 weeks during maintenance (up to week 52); induction placebo patients and week 6 nonresponders continued on placebo and VDZ 300 mg every 4 weeks, respectively. Endoscopic evaluation was performed at weeks 0, 6, and 52; blood samples for PK evaluation were collected at various time points. First, for all VDZ-treated patients (cohorts 1 and 2) with a week 6 Mayo Clinic endoscopic subscore, median week 6 VDZ trough concentrations were determined among patients with each endoscopic subscore (range, 0–3; higher scores indicate more active disease). Then, week 6 VDZ trough concentration quartiles and associated rates of mucosal healing (endoscopic subscore ≤1) were calculated. Finally, a population PK model4 was used to estimate individual VDZ clearance values for all VDZ-treated patients with a week 6 endoscopic subscore. At week 6, mucosal healing was more common among patients with higher measured VDZ trough concentrations (Table 1). Week 6 median measured VDZ trough concentrations were 34.5 μg/mL for patients with an endoscopic subscore of 0 (n = 55), 30.4 μg/mL for those with a subscore of 1 (n = 223), 24.0 μg/mL for those with a subscore of 2 (n = 224), and 19.6 μg/mL for those with a subscore of 3 (n = 188) (subscores unavailable for 3 patients). Median week 6 measured VDZ trough concentrations for patients with the highest endoscopic subscores were below the overall week 6 median for GEMINI 1 (25.6 μg/mL). A trend toward higher individual estimated VDZ clearance values in patients with higher endoscopic subscores was noted (Figure 1), suggestive of faster VDZ elimination in these patients. At week 6, endoscopic subscores were lower and mucosal healing was more common in patients with UC who had higher measured VDZ trough concentrations. The apparent association between higher endoscopic subscores and faster VDZ clearance could be attributable to several confounding factors and warrants further investigation. Additional analyses of the relationship between VDZ PK and endoscopic outcomes at week 52 of GEMINI 1 are ongoing. References 1. Paul S, et al. Inflamm Bowel Dis. 2013;19(12):2568–2576. 2. Roblin X, et al. Am J Gastroenterol. 2014;109(8):1250–1256. 3. Feagan BG, et al. N Engl J Med. 2013;369(8):699–710. 4. Rosario M, et al. J Crohns Colitis. 2014;8:S225–S226. The clinical study was funded by Millennium Pharmaceuticals, Inc. (d/b/a Takeda Pharmaceuticals International Co.). Medical writing assistance was provided by Elizabeth Barton of MedLogix Communications, LLC, and supported by Takeda Pharmaceuticals International, Inc. Sanhita Abrol assisted with the figures.