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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 (AUC0-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.

journal_name

Clin Drug Investig

journal_title

Clinical drug investigation

authors

Rosario M,Wyant T,Leach T,Sankoh S,Scholz C,Parikh A,Fox I,Feagan BG

doi

10.1007/s40261-016-0437-4

subject

Has Abstract

pub_date

2016-11-01 00:00:00

pages

913-923

issue

eissn

1173-2563

issn

1179-1918

pii

10.1007/s40261-016-0437-4

journal_volume

pub_type

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