TOFACITINIB POPULATION PHARMACOKINETICS IN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS: A POOLED ANALYSIS OF DATA FROM THREE CLINICAL STUDIES

Background: Tofacitinib is an oral JAK inhibitor that is being investigated for juvenile idiopathic arthritis (JIA). Objectives: To describe tofacitinib pharmacokinetics (PK) in patients with JIA, identify potential covariates accounting for variability in exposure, assess the formulation effect of oral solution vs tablet and propose a simplified dosing regimen. Methods: This was a pooled analysis of data from 3 tofacitinib clinical studies in patients with JIA aged 2− Results: Of 246 patients in the analysis, 74.0% were female; 87.8% were white, 2% were black, 10.2% were ‘other’ races and no patients were Asian. Median (range) BW was 46.3 (11.1−121.8) kg. Initially, 100 patients received oral solution and 146 patients received tablets; 11 patients switched formulations during the studies. A one compartment disposition model with first-order absorption and a lag time sufficiently described the data. Final estimates for CL/F, V/F and the first-order absorption rate constant (ka) for tablets were 26.1 L/hr, 89.2 L and 2.78 hr-1, respectively. The only statistically significant covariate was a formulation effect on ka. All parameters were estimated adequately. Estimated allometric exponents were 0.310 for CL/F and 0.537 for V/F. Absorption was described with an estimated lag time of 0.186 hr, and the oral solution had a 1.64-fold faster absorption rate vs the tablet. VPCs sufficiently described the observed data over time, across BWs and ages. Given the PK characterisation and variability in patients with JIA, a simplified dosing scheme was proposed, targeting Cavg values equivalent to those in patients receiving 5 mg BID: 3.2 mg BID solution in patients 10− Conclusion: Tofacitinib population PK in patients with JIA were adequately described by a one compartment model parameterised in terms of CL/F, V/F and first-order absorption with a lag time. Drug absorption from the oral solution was faster than from the tablet. Tofacitinib does not require dose modification or restrictions for any covariates, except BW, to account for differences in Cavg. Based on the results of this analysis, a simplified BW-based dosing regimen was proposed. Acknowledgments: Study sponsored by Pfizer Inc. Medical writing support was provided by Sarah Piggott of CMC Connect and funded by Pfizer Inc. Disclosure of Interests: Camille Vong Shareholder of: Pfizer Inc, at time of analysis, Employee of: Pfizer Inc, at time of analysis, Xiaoxing Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Anasuya Hazra Shareholder of: Pfizer Inc, at time of analysis, Employee of: Pfizer Inc, at time of analysis, Arnab Mukherjee Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Timothy Nicholas Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Cheng Chang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc