Maria Rosario1, Jonathan L French2, Nathanael L Dirks2, Serap Sankoh1, Asit Parikh1, Huyuan Yang1, Silvio Danese3, Jean-Frédéric Colombel4, Michael Smyth5, William J Sandborn6, Brian G Feagan7, Walter Reinisch8, Bruce E Sands4, Miguel Sans9, Irving Fox1. 1. Clinical Pharmacology Department, Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA. 2. Metrum Research Group LLC, Tariffville, CT, USA. 3. Inflammatory Bowel Disease Clinical and Research Unit, Istituto Clinico Humanitas, Milan, Italy. 4. Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA. 5. Takeda Development Centre Europe Ltd, London, UK. 6. Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. 7. Robarts Research Institute, University of Western Ontario, London, ON, Canada. 8. Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria, and Department of Internal Medicine, McMaster University, Hamilton, ON, Canada. 9. Digestive Diseases Service, Centro Médico Teknon, Barcelona, Spain.
Abstract
BACKGROUND AND AIMS: A positive relationship between vedolizumab trough serum concentrations and clinical outcomes in patients with ulcerative colitis [UC] or Crohn's disease [CD] has been reported. Here we further explore exposure-efficacy relationships for vedolizumab induction therapy in post hoc analyses of GEMINI study data. METHODS: Vedolizumab trough concentrations at Week 6 or 10 were grouped in quartiles and clinical outcome rates calculated. Exposure-efficacy relationships at Week 6 and potential baseline covariate effects were explored using logistic regression and individual predicted cumulative average concentration through Week 6 [Caverage] as exposure measure. RESULTS: Higher vedolizumab concentrations were associated with higher clinical remission rates; the exposure-efficacy relationship was steeper for UC than CD. Unadjusted analyses overestimated the relationship, more so for CD. From covariate-adjusted models, average probability of remission at Week 6 increased by approximately 15% for UC and 10% for CD between Caverage values of 35 and 84 µg/ml [5th and 95th percentiles, respectively]. On average, patients with higher albumin, lower faecal calprotectin [UC only], lower C-reactive protein [CD only], and no previous tumour necrosis factor-α [TNFα] antagonist use had a higher remission probability. Previous TNFα antagonist use had the greatest impact; remission probability was approximately 10% higher in treatment-naïve patients. CONCLUSIONS: Higher vedolizumab serum concentrations were associated with higher remission rates after induction therapy in patients with moderately to severely active UC or CD. This relationship is affected by several factors, including previous TNFα antagonist use. Prospective studies are needed to assess vedolizumab dose individualisation and optimisation.
BACKGROUND AND AIMS: A positive relationship between vedolizumab trough serum concentrations and clinical outcomes in patients with ulcerative colitis [UC] or Crohn's disease [CD] has been reported. Here we further explore exposure-efficacy relationships for vedolizumab induction therapy in post hoc analyses of GEMINI study data. METHODS: Vedolizumab trough concentrations at Week 6 or 10 were grouped in quartiles and clinical outcome rates calculated. Exposure-efficacy relationships at Week 6 and potential baseline covariate effects were explored using logistic regression and individual predicted cumulative average concentration through Week 6 [Caverage] as exposure measure. RESULTS: Higher vedolizumab concentrations were associated with higher clinical remission rates; the exposure-efficacy relationship was steeper for UC than CD. Unadjusted analyses overestimated the relationship, more so for CD. From covariate-adjusted models, average probability of remission at Week 6 increased by approximately 15% for UC and 10% for CD between Caverage values of 35 and 84 µg/ml [5th and 95th percentiles, respectively]. On average, patients with higher albumin, lower faecal calprotectin [UC only], lower C-reactive protein [CD only], and no previous tumour necrosis factor-α [TNFα] antagonist use had a higher remission probability. Previous TNFα antagonist use had the greatest impact; remission probability was approximately 10% higher in treatment-naïve patients. CONCLUSIONS: Higher vedolizumab serum concentrations were associated with higher remission rates after induction therapy in patients with moderately to severely active UC or CD. This relationship is affected by several factors, including previous TNFα antagonist use. Prospective studies are needed to assess vedolizumab dose individualisation and optimisation.
Authors: Parambir S Dulai; Brigid S Boland; Siddharth Singh; Khadija Chaudrey; Jenna L Koliani-Pace; Gursimran Kochhar; Malav P Parikh; Eugenia Shmidt; Justin Hartke; Prianka Chilukuri; Joseph Meserve; Diana Whitehead; Robert Hirten; Adam C Winters; Leah G Katta; Farhad Peerani; Neeraj Narula; Keith Sultan; Arun Swaminath; Matthew Bohm; Dana Lukin; David Hudesman; John T Chang; Jesus Rivera-Nieves; Vipul Jairath; G Y Zou; Brian G Feagan; Bo Shen; Corey A Siegel; Edward V Loftus; Sunanda Kane; Bruce E Sands; Jean-Frederic Colombel; William J Sandborn; Karen Lasch; Charlie Cao Journal: Gastroenterology Date: 2018-05-30 Impact factor: 22.682
Authors: Jurij Hanžel; Nejc Sever; Ivan Ferkolj; Borut Štabuc; Nataša Smrekar; Tina Kurent; Matic Koželj; Gregor Novak; Griet Compernolle; Sophie Tops; Ann Gils; David Drobne Journal: United European Gastroenterol J Date: 2019-03-19 Impact factor: 4.623