Population pharmacokinetics of tofacitinib in patients with active ankylosing spondylitis.

OBJECTIVE

To characterize tofacitinib pharmacokinetics (PK) in patients with active ankylosing spondylitis (AS) and estimate the effects of covariates on variability of PK parameters.

MATERIALS AND

METHODS

Pooled data from two studies in patients with AS who received tofacitinib were analyzed using nonlinear mixed-effects modeling. Tofacitinib PK was described by a one-compartment model parameterized in terms of apparent oral clearance (CL/F), apparent volume of distribution (V/F), and a first-order absorption rate constant (ka). Covariates evaluated: baseline age, sex, race, creatinine clearance (BCCL), and C-reactive protein for CL/F; baseline age/body weight for V/F.

RESULTS

Analysis included 279 patients. The point estimates for CL/F, V/F, and ka were 27.1 L/hour, 126 L, and 3.07 hour-1, respectively, in a reference patient. Excluding BCCL, point estimates of area under the concentration-time curve (AUC) over a dosing interval at steady-state and maximum steady-state tofacitinib concentration (Cmax) change vs. the reference patient ranged from 98 - 112% and 89 - 115%, respectively. Estimated AUC was 24% higher in a patient with BCCL = 50 mL/min vs. the reference patient (BCCL = 126 mL/min). Point estimates and 90% confidence intervals of the AUC and Cmax ratios indicated no major differences in tofacitinib exposure over the range of baseline age/body weight studied, and sex/race.

CONCLUSION

Tofacitinib does not require dose adjustment/restriction for age, body weight, sex, or race based on the differences (< 20%) in exposure relative to a reference patient with AS. The tofacitinib CL/F and BCCL relationship was consistent with known contribution of renal excretion to total tofacitinib clearance.