Reversibility of peripheral blood leukocyte phenotypic and functional changes after exposure to and withdrawal from tofacitinib, a Janus kinase inhibitor, in healthy volunteers

Bibliographische Detailangaben
Veröffentlicht in:	Clinical immunology (Orlando, Fla.). - 1999. - 191(2018) vom: 15. Juni, Seite 10-20
1. Verfasser:	Weinhold, Kent J (VerfasserIn)
Weitere Verfasser:	Bukowski, Jack F, Brennan, Todd V, Noveck, Robert J, Staats, Janet S, Lin, Liwen, Stempora, Linda, Hammond, Constance, Wouters, Ann, Mojcik, Christopher F, Cheng, John, Collinge, Mark, Jesson, Michael I, Hazra, Anasuya, Biswas, Pinaki, Lan, Shuping, Clark, James D, Hodge, Jennifer A
Format:	Online-Aufsatz
Sprache:	English
Veröffentlicht:	2018
Zugriff auf das übergeordnete Werk:	Clinical immunology (Orlando, Fla.)
Schlagworte:	Clinical Trial, Phase I Journal Article Research Support, Non-U.S. Gov't Cytotoxicity Healthy volunteers Interferon-γ Natural killer cells T cells Tofacitinib Janus Kinase Inhibitors mehr... Piperidines Pyrimidines Pyrroles tofacitinib 87LA6FU830

Beschreibung
Zusammenfassung:	Copyright © 2018 Pfizer Inc. Published by Elsevier Inc. All rights reserved. This study evaluated the short-term effects of tofacitinib treatment on peripheral blood leukocyte phenotype and function, and the reversibility of any such effects following treatment withdrawal in healthy volunteers. Cytomegalovirus (CMV)-seropositive subjects received oral tofacitinib 10 mg twice daily for 4 weeks and were followed for 4 weeks after drug withdrawal. There were slight increases in total lymphocyte and total T-cell counts during tofacitinib treatment, and B-cell counts increased by up to 26%. There were no significant changes in granulocyte or monocyte counts, or granulocyte function. Naïve and central memory T-cell counts increased during treatment, while all subsets of activated T cells were decreased by up to 69%. T-cell subsets other than effector memory cluster of differentiation (CD)4+, activated naïve CD4+ and effector CD8+ T-cell counts and B-cell counts, normalized 4 weeks after withdrawal. Following ex vivo activation, measures of CMV-specific T-cell responses, and antigen non-specific T-cell-mediated cytotoxicity and interferon (IFN)-γ production, decreased slightly. These T-cell functional changes were most pronounced at Day 15, partially normalized while still on tofacitinib and returned to baseline after drug withdrawal. Total natural killer (NK)-cell counts decreased by 33%, returning towards baseline after drug withdrawal. NK-cell function decreased during tofacitinib treatment, but without a consistent time course across measured parameters. However, markers of NK-cell-mediated cytotoxicity, antibody-dependent cellular cytotoxicity and IFN-γ production were decreased up to 42% 1 month after drug withdrawal. CMV DNA was not detectable in whole blood, and there were no cases of herpes zoster reactivation. No new safety concerns arose. In conclusion, the effect of short-term tofacitinib treatment on leukocyte composition and function in healthy CMV+ volunteers is modest and largely reversible 4 weeks after withdrawal
Beschreibung:	Date Completed 05.07.2019 Date Revised 05.07.2019 published: Print-Electronic Citation Status MEDLINE
ISSN:	1521-7035
DOI:	10.1016/j.clim.2018.03.002