title: Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn's disease.
abstract: BACKGROUND
  Vedolizumab, an anti-α(4)β(7) integrin monoclonal antibody (mAb), is indicated for treating patients with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). As higher therapeutic mAb concentrations have been associated with greater efficacy in inflammatory bowel disease, understanding determinants of vedolizumab clearance may help to optimise dosing.
  
  
  OBJECTIVE
  To characterise vedolizumab pharmacokinetics in patients with UC and CD, to identify clinically relevant determinants of vedolizumab clearance, and to describe the pharmacokinetic-pharmacodynamic relationship using population modelling.
  
  
  METHODS
  Data from a phase 1 healthy volunteer study, a phase 2 UC study, and 3 phase 3 UC/CD studies were included. Population pharmacokinetic analysis for repeated measures was conducted using nonlinear mixed effects modelling. Results from the base model, developed using extensive phase 1 and 2 data, were used to develop the full covariate model, which was fit to sparse phase 3 data.
  
  
  RESULTS
  Vedolizumab pharmacokinetics was described by a 2-compartment model with parallel linear and nonlinear elimination. Using reference covariate values, linear elimination half-life of vedolizumab was 25.5 days; linear clearance (CL(L)) was 0.159 L/day for UC and 0.155 L/day for CD; central compartment volume of distribution (V(c)) was 3.19 L; and peripheral compartment volume of distribution was 1.66 L. Interindividual variabilities (%CV) were 35% for CLL and 19% for V(c); residual variance was 24%. Only extreme albumin and body weight values were identified as potential clinically important predictors of CL(L).
  
  
  CONCLUSIONS
  Population pharmacokinetic parameters were similar in patients with moderately to severely active UC and CD. This analysis supports use of vedolizumab fixed dosing in these patients. Clinicaltrials.gov Identifiers: NCT01177228; NCT00783718 (GEMINI 1); NCT00783692 (GEMINI 2); NCT01224171 (GEMINI 3).
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Rosario
authors.affiliation: Metrum Research Group LLC, Tariffville, CT, USA.
authors.forename: N L
authors.initials: NL
authors.lastname: Dirks
authors.affiliation: Metrum Research Group LLC, Tariffville, CT, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Gastonguay
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Fasanmade
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Wyant
authors.affiliation: Takeda Pharmaceuticals International, Inc., Deerfield, IL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Parikh
authors.affiliation: Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Sandborn
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, ON, Canada.
authors.forename: B G
authors.initials: BG
authors.lastname: Feagan
authors.affiliation: Department Internal Medicine III, Medical University of Vienna, Vienna, Austria.|Department of Internal Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Reinisch
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Fox
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000418:Albumins / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001835:Body Weight; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D003424:Crohn Disease / Q000188:drug therapy*; D005260:Female; D005765:Gastrointestinal Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000418:Albumins; D061067:Antibodies, Monoclonal, Humanized; D005765:Gastrointestinal Agents; C543529:vedolizumab