Background/Purpose: Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The efficacy and safety of an immediate-release (IR) formulation of tofacitinib, dosed twice daily (BID), has been assessed in patients with active moderate to severe RA. A once daily (QD) posology of tofacitinib will enhance patient convenience, ease of use, and has the potential to optimize compliance.¹ To facilitate QD dosing, a novel modified-release (MR) formulation of tofacitinib at a dose of 11 mg has been designed to achieve comparability of systemic exposure parameters vs IR 5 mg BID. The study aimed to determine equivalence for extent of exposure between the tofacitinib MR 11 mg vs IR formulation administered as two 5 mg tablets.

Methods: This was a randomized, open-label, 2-period, 2-sequence crossover study conducted in 26 healthy volunteers (HV). Following an overnight fast, HV were randomized to receive single doses of either MR 11 mg or IR 2 x 5 mg. Treatments were separated by a 72-hour (h) washout. Pharmacokinetic (PK) parameters were calculated using non-compartmental analyses (NCA). The primary endpoint was extent of tofacitinib exposure, measured as area under the concentration-time curve from time zero extrapolated to infinite time (AUC_inf). A mixed-effects model was used to generate adjusted geometric mean ratios (MR/IR) and 90% confidence intervals (CIs). The steady-state profiles of tofacitinib MR and IR were predicted using single-dose data from this study.

Results: All 26 HV completed the study and were included in the analyses. The study population had mean age of 33.6 years, mean body weight of 77.5 kg, and was 81% male. For the MR and IR formulations, geometric mean AUC_inf (ng*h/mL) was 297.5 and 286.3, respectively, resulting in an MR/IR ratio of 103.91% (90% CI 100.49%, 107.45%). Maximum plasma concentration adjusted for formulation (C_{max, adj}; ng/mL) was 40.75 and 44.10 for MR and IR, respectively, resulting in an MR/IR ratio of 92.40% (90% CI 84.99%, 100.45%). For both parameters, 90% CI values were wholly contained within the 80–125% interval. Mean terminal half-life was 5.71 h and 3.41 h for MR and IR formulations, respectively. The most common AEs were nausea, abdominal pain, back pain, and headache. Incidence of AEs was similar between treatment groups and no serious or severe AEs were reported. Predictions following steady-state dosing indicate similar AUC, peak concentration and minimum concentration values, and similar time above JAK1/3 half-maximal inhibitory concentration signaling thresholds between MR and IR formulations.

Conclusion: This study demonstrates the single dose equivalence of AUC_inf and C_{max, adj} of the MR and IR formulations of tofacitinib. Single doses of both formulations were well tolerated. This novel MR formulation of tofacitinib facilitates an opportunity to enable QD dosing, while maintaining systemic drug concentrations similar to the IR formulation (administered BID). Multiple-dose studies will be conducted to confirm the steady-state PK profile predictions and demonstrate equivalence between formulations following steady-state dosing.

1. Coleman CI et al. J Manag Care Pharm 2012; 18: 527-39.