Introduction: Tofacitinib is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator. Tofacitinib achieved comparable rate of biopsy-proven acute rejection and improved renal function compared with cyclosporine (CsA) in a Phase 2b study in de novo kidney transplant (KT) patients. The objective of this analysis was to characterize the pharmacokinetics (PK) of tofacitinib in de novo KT patients with a focus on 1) obtaining population parameters as well as interindividual (IIV) and residual variability estimates; 2) characterizing time-dependency, if any, in oral clearance (CL/F); 3) identifying covariates that are important determinants of systemic exposure.

Methods: There were 192 patients who received treatment with either 1 of 2 fixed-doses of tofacitinib included in the analysis. A one-compartmental model was developed using a nonlinear mixed effects modeling approach with NONMEM version 7.1.2. IIV was modeled using exponential random effects. Residual variability was estimated separately for samples collected between 1.5 and 2.5 hours post-dose and samples collected outside of this time window. Time-dependency in tofacitinib CL/F was assessed using a piecewise model. A full covariate modeling approach was used to test covariates (weight, sex, age and geographic region on CL/F; age and weight on volume of distribution [V/F]).

Results: Tofacitinib PK was well described using a one-compartment model with first-order absorption. The population parameter estimates (and IIV expressed as % coefficient of variation) in the base model were: CL/F, 22.0 L/hr (29%); V/F, 119 L (19%); half-life, 3.79 hr (17%). Residual variability for samples collected between 1.5 and 2.5 hours post-dose was 39% and was 62% for samples collected outside of this time window. Analysis revealed a lack of time-dependency using a linear model during the first 6 months of treatment; hence this was not included in the final model. Mean CL/F decreased from 19.2 L/hr for a patient with a median age of 47 years to 17.2 L/hr in an older patient of 65 years. There was no effect of weight, sex, race, or geographic region on tofacitinib CL/F.

Conclusions: The PK population parameter estimates of tofacitinib in transplant patients were well described in this analysis. Based on the full covariate modeling approach, tofacitinib does not require a dose modification for age, body weight, gender, or geographic region in transplant patients.

Tortorici, M.: Employee, Pfizer Inc. Stockholder, Pfizer Inc. Lamba, M.: Employee, Pfizer Inc. Stockholder, Pfizer Inc. Chan, G.: Employee, Pfizer Inc. Stockholder, Pfizer Inc. Krishnaswami, S.: Employee, Pfizer Inc. Stockholder, Pfizer Inc.

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