Population Pharmacokinetics of Tofacitinib in Patients With Moderate to Severe Ulcerative Colitis

Abstract

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We characterized tofacitinib pharmacokinetics in patients with moderate to severe UC, and the effects of covariates on variability in pharmacokinetic parameter estimates. Data were pooled from 1 8‐week phase 2 and 2 8‐week phase 3 induction studies, and a 52‐week phase 3 maintenance study (N = 1096). Population pharmacokinetic analysis was conducted using nonlinear mixed‐effects modeling. Potential predictors of apparent oral clearance (CL/F) and volume of distribution (V/F) were evaluated. The PK was described by a 1‐compartment model parameterized in terms of CL/F (26.3 L/hour [h]) and V/F (115.8 L), with first‐order absorption (Ka; 9.85 h−1) and lag time (0.236 h). The derived elimination half‐life was approximately 3.05 h. In the final model, baseline creatinine clearance, sex, and race (Asian vs non‐Asian) were significant covariates for CL/F; significant covariates for V/F were age, sex, and body weight; baseline albumin and baseline Mayo score were not significant covariates. CL/F between‐patient variability was estimated at 22%. Tofacitinib exposure did not change significantly over the duration of induction/maintenance treatment in patients with UC. Although statistically significant covariate effects on CL/F and V/F were observed, the magnitude of the effects are not clinically significant. Therefore, dose adjustment/restrictions for age, body weight, sex, race, or baseline disease severity are not required during tofacitinib treatment. ClinicalTrials.gov numbers: NCT00787202, NCT01465763, NCT01458951, NCT01458574.

Exposure‐Response Characterization of Tofacitinib Efficacy in Moderate to Severe Ulcerative Colitis: Results From Phase II and Phase III Induction and Maintenance Studies

“…Use of C avg as the predictor is consistent with E‐R model predictions for tofacitinib in rheumatoid arthritis 15 . Plasma concentrations of tofacitinib have been shown to be stable long‐term in patients with UC, providing there is no change in dose 11 . In contrast, biologic therapies can be susceptible to clearance mechanisms that result in low drug exposure and subsequent loss of response in some patients 12 .…”

“…The geometric mean C avg at 10 mg b.i.d. (33.6 ng/mL; derived from previously reported PK parameters) 11 corresponded to ED 67 on the E‐R curve for remission.…”

“…Individual PK parameters for exposure index were reported previously 11 . Average and trough concentrations (C avg and C trough , respectively) were derived from the dose‐normalized, individual empirical Bayes estimates obtained from the population PK model.…”

“…Tofacitinib PKs were linear, with a dose‐proportional increase in exposure. Oral clearance of tofacitinib did not change significantly over time, and dose adjustments for age, weight, sex, race, or baseline disease severity were not required 11 . In the phase II study, baseline disease activity was the most important predictor of efficacy 12 …”

Small Molecule Drugs in Inflammatory Bowel Diseases

“…A study on tofacitinib’s pharmacokinetics showed that no significant change in tofacitinib exposure (apparent oral clearance) was seen over the duration of treatment. Additionally, age, sex, body weight, and baseline disease severity had no clinically significant impact on the apparent oral clearance and volume of distribution, indicating no need to adjust the dose of tofacitinib [ 62 ].…”