Vedolizumab Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability Following Administration of a Single, Ascending, Intravenous Dose to Healthy Volunteers

Abstract

Background and objectives: Vedolizumab, a humanized monoclonal antibody against the α₄β₇ integrin, 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 α₄β₇ saturation 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 (C _max) 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 (AUC_0-inf) and shorter terminal elimination half-life (t _1/2) 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 α₄β₇ was 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 α₄β₇ saturation was observed at all doses. A single intravenous infusion of vedolizumab was well tolerated by healthy volunteers.