Exposure-response characterisation of tofacitinib efficacy in moderate to severe ulcerative colitis: results from a dose-ranging phase 2 trial

SUMMARY

BACKGROUND AND AIMS

Tofacitinib is an oral, small molecule JAK inhibitor being investigated for UC. In a phase 2 dose-ranging study, tofacitinib demonstrated efficacy vs placebo as UC induction therapy. In this post-hoc analysis, we aimed to compare tofacitinib dose and plasma concentration as predictors of efficacy and identify covariates that determined efficacy in patients with UC.

METHODS

One- and two-compartment pharmacokinetic models, with first-order absorption and elimination, were evaluated to describe plasma tofacitinib concentration-time data at baseline and week 8. Relationships between tofacitinib exposure (dose, C_av,ss and C_trough,ss) and week 8 efficacy endpoints were characterised using logistic regression analysis. Baseline disease, demographics, prior and concurrent UC treatment were evaluated as covariates.

RESULTS

Plasma tofacitinib concentrations increased proportionately with dose and estimated oral clearance, and C_av,ss values were not significantly different between baseline and week 8. Dose, C_av,ss and C_trough,ss performed similarly as predictors of efficacy based on statistical criteria for model fit and comparison of model predictions for each endpoint. Individual C_av,ss values were similar between clinical remitters and non-remitters at predicted efficacious doses (10 and 15 mg twice daily [b.d.]). Baseline Mayo score was a significant determinant of efficacy. Predicted differences from placebo in clinical remission at 10 mg b.d. for patients with baseline Mayo score >8 and ≤8 were 39% (95% CI: 7–70) and 21% (-2–50), respectively.

CONCLUSIONS

Exposure-response characterisation demonstrated the potential of tofacitinib 10 and 15 mg b.d. as induction therapy for UC without monitoring of plasma drug concentrations for dose optimisation.

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