title: Vedolizumab Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability Following Administration of a Single, Ascending, Intravenous Dose to Healthy Volunteers.
abstract: OBJECTIVE
  Vedolizumab, a humanized monoclonal antibody against the α4β7integrin, is indicated for treatment of moderately to severely active ulcerative colitis or Crohn's disease. In this placebo-controlled, double-blind, randomized, single ascending-dose study, the pharmacokinetics, pharmacodynamics, safety, and tolerability of vedolizumab were evaluated in healthy volunteers.
  
  
  METHODS
  Forty-nine participants (in five cohorts) were randomly assigned in a 4:1 ratio to receive a single intravenous infusion of either vedolizumab (0.2, 0.5, 2.0, 6.0, or 10.0 mg/kg) or placebo. Blood samples were collected for measurement of vedolizumab serum concentrations and α4β7saturation on peripheral blood lymphocytes by vedolizumab. Pharmacokinetic parameters were computed using a non-compartmental approach. Adverse events were monitored.
  
  
  RESULTS
  Vedolizumab maximum observed serum concentration (Cmax) demonstrated dose proportionality over the dose range tested. Greater than dose-proportional increases in area under the serum concentration-time curve from time 0 to infinity (AUC0-inf) and shorter terminal elimination half-life (t1/2) were observed from 0.2 to 2.0 mg/kg, suggestive of nonlinear pharmacokinetics at lower doses. At doses higher than 2.0 mg/kg, these parameters increased dose proportionally. Saturation of α4β7was at or near maximal levels (>90 %) at all doses and time points when vedolizumab was measurable in serum. A total of 21 of 39 (54 %) vedolizumab-treated participants were anti-drug antibody (ADA) positive, and 11 (28 %) were persistently ADA positive. Overall, no adverse event signals, including serious infections or malignancies, were apparent.
  
  
  CONCLUSIONS
  Vedolizumab exhibited target-mediated disposition, characterized by a rapid, saturable, nonlinear elimination process at low concentrations and a slower linear elimination process at higher concentrations. Nearly complete α4β7saturation was observed at all doses. A single intravenous infusion of vedolizumab was well tolerated by healthy volunteers.
authors.affiliation: Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company, Ltd.), Cambridge, MA, USA. maria.rosario@takeda.com.
authors.forename: Maria
authors.initials: M
authors.lastname: Rosario
authors.affiliation: Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company, Ltd.), Cambridge, MA, USA.|Curis, Inc., Lexington, MA, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Wyant
authors.affiliation: Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company, Ltd.), Cambridge, MA, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Leach
authors.affiliation: Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company, Ltd.), Cambridge, MA, USA.
authors.forename: Serap
authors.initials: S
authors.lastname: Sankoh
authors.affiliation: Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company, Ltd.), Cambridge, MA, USA.|Kura Oncology, Inc., Cambridge, MA, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Scholz
authors.affiliation: Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company, Ltd.), Cambridge, MA, USA.
authors.forename: Asit
authors.initials: A
authors.lastname: Parikh
authors.affiliation: Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company, Ltd.), Cambridge, MA, USA.
authors.forename: Irving
authors.initials: I
authors.lastname: Fox
authors.affiliation: Robarts Research Institute, University of Western Ontario, London, ON, Canada.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Feagan
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C543529:vedolizumab