Camille Vong (1), Chenhui Deng (2); Rujia Xie (2); Steven W. Martin (1); Dahong Yu (4); Deborah A Woodworth (4); Wojciech Niezychowski (4); Chinyu Su (4); Arnab Mukherjee (3)
Pfizer Inc, (1) Cambridge, MA, United States (2) Shanghai, China (3) Groton, CT, United States (4) Collegeville, PA, United States.
Objectives: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). The objectives of this analysis were to develop a population PK model of tofacitinib using pooled data from Phase 2 and 3 studies and evaluate the possible relationship between exposure and covariates.
Methods: Data from 1054 patients (median age: 41 years; median weight: 74 kg; median baseline Mayo score: 9) receiving tofacitinib either as 0.5, 3, 10 or 15 mg twice daily (BID) were analyzed using FOCE with Interaction in NONMEM. The following patient characteristics were assessed as covariates on PK parameters using a full model approach: race, sex, age, body weight, baseline creatinine clearance, baseline C-reactive protein, baseline albumin, ethnicity and use of concomitant medication (oral steroids and 5-ASA). Single imputation method based on the remaining available data was used for proportion of missing covariates less than 10% (case for all exploratory covariates, except ethnicity that was excluded from the covariate analysis). 4.5% of total concentrations were BLQ and excluded from the analysis. Goodness of fit plots and visual prediction checks were used for model selection and evaluation. Bootstraps were applied to identify significant covariate effects in the full covariate model.
Results: The PK of tofacitinib exhibits linear PK and was best characterized by a one-compartment first-order absorption model with an absorption lag time of 0.23 hr. Mean (RSE %) estimated PK parameters for a typical study subject were apparent clearance (CL/F) of 25 L/hr (1.13), apparent volume of distribution (V/F) of 108 L (1.12) and first-order absorption rate constant (Ka) of 9.31 hr-1(8.63). Correlation between CL/F and V/F was estimated at 0.261. Inter-individual variability (ISV) (RSE %) estimated for CL/F was 24.6 % (8.55) and an Inter-occasion variability (IOV) for Ka was 179% (7.49). The full model included covariate relationships of creatinine clearance and race on clearance while significant covariates for volume were age and body weight.
Conclusions: The proposed model adequately describes tofacitinib plasma PK that was found consistent between phase 2 and 3 studies. This model will be used in the next step to evaluate the exposure-response correlation between tofacinitib exposure and primary and secondary endpoints of remission and mucosal healing at Week 8 (central read) based on Mayo scores.
References:
[1] Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 2010; 105:501-23.
[2] Meyer DM, et al., Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm (Lond). 2010. 11; 7:41.
[3] Murray PJ, The JAK-STAT signaling pathway: input and output integration. J Immunol. 2007. 178(5): 2623-9.
[4] Gastonguay MR, A Full Model Estimation Approach for Covariate Effects: Inference Based on Clinical Importance and Estimation Precision. Abstract at 2004 AAPS Annual Meeting.
Reference: PAGE 25 (2016) Abstr 5960 [www.page-meeting.org/?abstract=5960]
Poster: Drug/Disease modeling - Other topics