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P428 Tofacitinib pharmacokinetics and durability of drug exposure in moderate-to-severe Crohn’s disease patients in Phase 2 induction and maintenance studies

A. Mukherjee1, C. Deng2, R. Xie2, S.W. Martin3, G. Chan4, M. Moscariello4, W. Niezychowski4, E. Maller*4

1Pfizer Inc, Groton, United States, 2Pfizer Inc, Shanghai, China, 3Pfizer Inc, Cambridge, United States, 4Pfizer Inc, Collegeville, Pennsylvania, United States

Background

Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for inflammatory bowel disease. Here we characterised the pharmacokinetics of tofacitinib in patients with moderate-to-severe Crohn’s disease (CD); we also evaluated durability of exposures during the course of 2 randomised, double-blind, placebo-controlled, multicentre Phase 2b studies with tofacitinib 5 or 10 mg twice daily (BID).

Methods

Subjects in the 8-week induction study were randomised to placebo or tofacitinib 5 or 10 mg BID. Subjects meeting predefined efficacy criteria in the induction study were re-randomised 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, and race), baseline creatinine clearance (BCCL), baseline CRP (BCRP), and baseline faecal 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, and 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 Cavg and Ctrough values, summarised over time (Figure 1), further supported the durability of tofacitinib exposure.

Conclusion

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

Figure 1.