Tofacitinib Pharmacokinetics in Moderate-to-Severe Crohn’s Disease Patients in Phase 2 Induction and Maintenance Studies

Aims: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for inflammatory bowel disease. The aims of this analysis were to characterize the pharmacokinetics of tofacitinib in patients with moderate to severe Crohn’s disease (CD) and to evaluate durability of exposures during the course of two randomized, double-blind, placebo-controlled, multi-center Phase 2b studies with tofacitinib 5 or 10 mg twice daily (BID).


Methods: Subjects in the 8-week induction study were randomized to placebo, tofacitinib 5 mg or 10 mg BID. Subjects meeting pre-defined efficacy criteria in the induction study were re-randomized to placebo, tofacitinib 5 mg BID, or 10 mg BID in the 26-week maintenance study. Plasma samples for the pharmacokinetic (PK) analysis were collected at baseline and Week 8 of the induction study, and Week 12 and 26 of the maintenance study. At each visit, 5 PK samples were collected from each subject. A population PK analysis was performed using NONMEM version 7.2 to describe the plasma concentration-time data and derive predicted exposure metrics, average concentration (Cavg) and trough concentration (Ctrough). Covariates evaluated on model parameters included demographics (age, weight, gender, race), baseline creatinine clearance (BCCL), baseline CRP (BCRP), and baseline fecal calprotectin (BFCP).


Results: The PK analysis included 184 subjects from induction and 108 subjects from maintenance who received at least 1 dose of tofacitinib and had at least 1 measurable concentration. Plasma concentration-time data were described using a 1-compartment model with first order absorption, absorption lag time, and first order elimination. Parameter estimates for a typical subject (38-year old Caucasian male, body weight 68.6 kg, BCCL=112.4 mL/min, BCRP=5.9 mg/L, BFEC=360 mg/kg) were, oral clearance (CL/F)=23.8 L/hr and oral volume of distribution (V/F)=97.5 L. Inter-subject variability (coefficient of variation) in CL/F was 30.3%. V/F showed a significant positive correlation with body weight. CL/F was not influenced by any evaluated covariate, tofacitinib dose, or time on treatment, indicating that Cavg increased proportionately with dose and did not change over the duration of treatment. Individual, dose-normalized Cavg and Ctrough values summarized over time  ADDIN EN.CITE
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(Figure 1) further supported the durability of tofacitinib exposure.


Conclusion: Tofacitinib PK characterization in CD patients indicated dose-proportional and durable exposure over the course of induction and maintenance therapy.