Exposure-efficacy Relationships for Vedolizumab Induction Therapy in Patients with Ulcerative Colitis or Crohn's Disease.
OBJECTIVE
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.
Clinical Pharmacology Department, Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA.
Maria
M
Rosario
Metrum Research Group LLC, Tariffville, CT, USA.
Jonathan L
JL
French
Metrum Research Group LLC, Tariffville, CT, USA.
Nathanael L
NL
Dirks
Clinical Pharmacology Department, Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA.
Serap
S
Sankoh
Clinical Pharmacology Department, Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA.
Asit
A
Parikh
Clinical Pharmacology Department, Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA.
Huyuan
H
Yang
Inflammatory Bowel Disease Clinical and Research Unit, Istituto Clinico Humanitas, Milan, Italy.
Silvio
S
Danese
Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA.
Jean-Frédéric
JF
Colombel
Takeda Development Centre Europe Ltd, London, UK.
Michael
M
Smyth
Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA.
William J
WJ
Sandborn
Robarts Research Institute, University of Western Ontario, London, ON, Canada.
Brian G
BG
Feagan
Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria, and Department of Internal Medicine, McMaster University, Hamilton, ON, Canada.
Walter
W
Reinisch
Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA.
Bruce E
BE
Sands
Digestive Diseases Service, Centro Médico Teknon, Barcelona, Spain.
Miguel
M
Sans
Clinical Pharmacology Department, Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA.
Irving
I
Fox
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D003424:Crohn Disease / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005243:Feces / Q000737:chemistry; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D039841:Leukocyte L1 Antigen Complex / Q000032:analysis; D008297:Male; D008875:Middle Aged; D012074:Remission Induction / Q000379:methods; D012709:Serum Albumin / Q000032:analysis; D016896:Treatment Outcome; D055815:Young Adult
D061067:Antibodies, Monoclonal, Humanized; D005765:Gastrointestinal Agents; D039841:Leukocyte L1 Antigen Complex; D012709:Serum Albumin; C543529:vedolizumab
Crohn’s disease; Ulcerative colitis; exposure–efficacy relationship; vedolizumab