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

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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.

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Acknowledgments

We thank the staff at Anapharm (Montréal, Quebec, Canada) for conducting the study and collecting the study data. We are grateful to the volunteers who participated in this study.

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Author notes

  1. Timothy Wyant

    Present address: Curis, Inc., Lexington, MA, USA

  2. Catherine Scholz

    Present address: Kura Oncology, Inc., Cambridge, MA, USA

Authors and Affiliations

  1. Millennium Pharmaceuticals, Inc. (a wholly owned subsidiary of Takeda Pharmaceutical Company, Ltd.), Cambridge, MA, USA

    Maria Rosario, Timothy Wyant, Timothy Leach, Serap Sankoh, Catherine Scholz, Asit Parikh & Irving Fox

  2. Robarts Research Institute, University of Western Ontario, London, ON, Canada

    Brian G. Feagan

Authors
  1. Maria Rosario
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  2. Timothy Wyant
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  3. Timothy Leach
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  4. Serap Sankoh
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  5. Catherine Scholz
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  6. Asit Parikh
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  7. Irving Fox
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  8. Brian G. Feagan
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Corresponding author

Correspondence to Maria Rosario.

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Funding

This clinical study was supported by Takeda. Writing assistance was provided by Elisabeth R. Wann, PhD, Wann Medical Communications, LLC, Wilmette, Illinois, USA, and was supported by Takeda Development Center Americas, Inc., Deerfield, Illinois, USA.

Conflict of interest

Maria Rosario, Timothy Leach, Serap Sankoh, Asit Parikh, and Irving Fox are employees of Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company, Ltd. Asit Parikh owns stock of Takeda Pharmaceutical Company, Ltd. Catherine Scholz and Timothy Wyant were employees of Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company, Ltd., at the time that this study was conducted. Catherine Scholz is co-inventor of Patent 13/462,414. Brian G. Feagan has served as a consultant, advisory board member, or speaker for Abbott/AbbVie, Actogenix, Albireo Pharma, Amgen, AstraZeneca, Avaxia Biologics Inc., Avir Pharma, Axcan, Baxter Healthcare Corp., Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharmaceuticals, Roche/Genentech, GiCare Pharma, Gilead, Given Imaging Inc., GlaxoSmithKline, Ironwood Pharmaceuticals, Janssen Biotech (Centocor), JnJ/Janssen, Kyowa Hakko Kirin Co., Ltd., Lexicon, Lilly, Lucera BioTech, Merck, Mesoblast Pharma, Millennium, Nektar, Nestles, Novo Nordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist, Receptos, Salix Pharmaceuticals, Serono, Shire, Sigmoid Pharma, Synergy Pharmaceuticals Inc., Takeda, Teva Pharmaceutical, TiGenix, Tillotts, UCB Pharma, Vertex Pharmaceuticals, VHsquared Ltd., Warner Chilcott, Wyeth, Zealand, and Zyngenia; and has received research funding from Abbott/AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen Biotech (Centocor), JnJ/Janssen, Roche/Genentech, Millennium, Pfizer, Receptos, Santarus, Sanofi, Tillotts, and UCB Pharma.

Ethical approval

This study was conducted in accordance with the ethical principles originating in or derived from the Declaration of Helsinki and its amendments, International Conference on Harmonization Good Clinical Practice Guidelines, and locally applicable laws or regulations. The protocol and informed consent form were approved by the institutional review board at the study site.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Rosario, M., Wyant, T., Leach, T. et al. Vedolizumab Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability Following Administration of a Single, Ascending, Intravenous Dose to Healthy Volunteers. Clin Drug Investig 36, 913–923 (2016). https://doi.org/10.1007/s40261-016-0437-4

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  • DOI: https://doi.org/10.1007/s40261-016-0437-4

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