Intestinally-restricted Janus Kinase inhibition: a potential approach to maximize the therapeutic index in inflammatory bowel disease therapy

Journal of Inflammation

Eva Situ¹  Melissa Ho¹  Melanie Kleinschek¹  Patrick Brassil²  Pam R. Tsuruda³  M. Teresa Pulido-Rios³  Sharath Hegde³  David T. Beattie³  Fei Shen³ 

[1]Department of Biology, Theravance Biopharma US, Inc

[2]Department of Drug Metabolism and Pharmacokinetics, Theravance Biopharma US, Inc

[3]Department of Pharmacology , Theravance Biopharma US, Inc

关键词: Inflammatory bowel disease;    Tofacitinib;    Janus kinase inhibitor;    Pharmacokinetics;    Pharmacodynamics;   

DOI  :  10.1186/s12950-017-0175-2

来源: DOAJ

【 摘 要 】

Abstract Background An unmet need remains for safe and effective treatments to induce and maintain remission in inflammatory bowel disease (IBD) patients. The Janus kinase (JAK) inhibitor, tofacitinib, has demonstrated robust efficacy in ulcerative colitis patients although, like other systemic immunosuppressants, there may be safety concerns associated with its use. This preclinical study evaluated whether modulating intestinal inflammation via local JAK inhibition can provide efficacy without systemic immunosuppression. Methods The influence of tofacitinib, dosed orally or intracecally, on oxazolone-induced colitis, oxazolone or interferon-γ (IFNγ)-induced elevation of colonic phosphorylated signal transducer and activator of transcription1 (pSTAT1) levels, and basal splenic natural killer (NK) cell counts was investigated in mice. Results Tofacitinib, dosed orally or intracecally, inhibited, with similar efficacy, oxazolone-induced colitis, represented by improvements in the disease activity index and its sub-scores (body weight, stool consistency and blood content). Intracecal dosing of tofacitinib resulted in a higher colon:plasma drug exposure ratio compared to oral dosing. At equieffective oral and intracecal doses, colonic levels of tofacitinib were similar, while the plasma levels for the latter were markedly lower, consistent with a lack of effect on splenic NK cell counts. Tofacitinib, dosed orally, intracecally, or applied to the colonic lumen in vitro, produced dose-dependent, and maximal inhibition of oxazolone or IFNγ-induced STAT1 phosphorylation in the colon. Conclusions Localized colonic JAK inhibition, by intracecal delivery of tofacitinib, provides colonic target engagement and efficacy in a mouse colitis model at doses which do not impact splenic NK cell counts. Intestinal targeting of JAK may permit separation of local anti-inflammatory activity from systemic immunosuppression, and thus provide a larger therapeutic index compared to systemic JAK inhibitors.

【 授权许可】

Unknown