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* = Presenting author

P036 Colon targeted delivery of tofacitinib inhibits oxazolone-induced colitis in mice, despite low systemic exposure

F. Shen*, P. Brassil, S. Hegde, D. Beattie

Theravance Biopharma, South San Francisco, California, United States

Background

Proinflammatory cytokines, acting via the Janus kinase (JAK) family of tyrosine kinases, are implicated in the pathogenesis of inflammatory bowel disease (IBD). Tofacitinib (Xeljanz®), an oral, systemically available, JAK inhibitor, is efficacious in moderate to severe ulcerative colitis (UC) patients (Sandborn et al., 2012). However, dose-limiting immunosuppression may be a concern with systemically available JAK inhibitors. This preclinical study addressed whether systemic JAK inhibition is essential for anticolitic activity.

Methods

The murine oxazolone colitis model was used as it shares many features of UC in patients (Boirivant et al., 1998). Tofacitinib was dosed orally or intracecally, via an indwelling cecal cannula, and its anticolitic activity, together with colon and plasma drug levels, were measured. Male Balb/C mice were sensitised by dermal application of oxazolone (4%), and then challenged intrarectally with oxazolone (1%) or vehicle, 7 days later. Tofacitinib or vehicle dosing was initiated 1 day before the oxazolone challenge. Two days after the oxazolone challenge, the disease activity index (DAI) was determined (an average of body weight loss, stool consistency, and occult blood scores). Colon and plasma concentrations of tofacitinib were measured at its Tmax.

Results

Oxazolone, but not its vehicle, increased the DAI. Oral dosing of tofacitinib (5–30 mg/kg TID, or 5 and 15 mg/kg, taken 2 times a day) produced a dose-dependent attenuation, with a maximal inhibition of 70% to 100%, of the oxazolone-induced increase in DAI. Intracecal tofacitinib (1 mg/kg BID) attenuated the DAI to a similar degree as that following the 15 mg/kg BID oral dose, at a similar colonic exposure (mean concentrations [± SEM] of 2 128 ± 693 and 16 56 ± 355 ng/g, respectively). The 1 mg/kg intracecal tofacitinib dose, however, was associated with a significantly lower systemic level compared with that following the 15 mg/kg oral dose (mean concentrations [± SEM] of 17 ± 1 and 1 314 ± 179 ng/mL, respectively). Oral tofacitinib (5 mg/kg BID) was inactive despite achieving a higher systemic exposure than that following intracecal tofacitinib (1 mg/kg BID), with mean concentrations [± SEM] of 216 ± 37 and 17 ± 1 ng/mL, respectively).

Conclusion

Local JAK inhibition in the colon may be sufficient to achieve efficacy in the murine oxazolone-induced colitis model. A locally acting JAK inhibitor, with limited systemic exposure, may maximise clinical efficacy in IBD, while minimising adverse effects arising from systemic immunosuppression.