LAUSR

Statement of Purpose, Innovation, or Hypothesis Itacitinib is a JAK-1 inhibitor currently in phase III development for the treatment of acute and chronic graft versus host disease (GVHD) in combination with corticosteroids. Itacitinib is primarily metabolized by CYP3A4 with minimal renal clearance. The purpose of the population pharmacokinetic analysis is to identify predictors of exposure and, if significant predictors are identified, optimize the dosing regimen in sub-populations with altered PK. Description of Methods and Materials The dataset contained itacitinib plasma concentrations collected from studies in healthy participants and patients with rheumatoid arthritis, plaque psoriasis, myelofibrosis, and acute graft-versus-host disease. An empiric compartmental model was developed to describe the pharmacokinetics of itacitinib and the following possible time-invariant sources of variability were explored: age, body weight, BMI, sex, race, ethnicity, renal and hepatic function, per protocol fed/fasted status, participant population, and albumin. Co-administration of CYP3A4 inhibitors or inducers, P-gp inhibitors, and gastric pH modifying agents were also explored as time-variant covariates. Data and Results The final dataset contained 3686 PK samples from 321 participants, of which 55.1% were male, 85.4% were white, and the median age and body weight were 46 y and 77.7 kg. 18 subjects were on a potent CYP3A4 inhibitor with most specifically on posaconazole. Sufficient data were not available to evaluate severe renal impairment or moderate or severe hepatic impairment. The structural model of itacitinib is a two-compartment model with first –order elimination and nonlinear absorption with dual first-order absorption pathways with lag-times. All population parameters include log-normal random effects except the parameter describing the fraction of the dose absorbed through each pathway which includes logit-normal random effect. The only predictors of itacitinib exposure identified were co-administration of potent CYP3A4 inhibitors, which decreased clearance by 39%, and participant population of which patients had a 38% lower clearance than healthy participants. Interpretation, Conclusion, or Significance A 39% decrease in clearance results in a 64% increase in exposure which is not considered clinically relevant based on cumulative safety data and the risk/benefit profile. Patients receiving CYP3A4 inhibitors which are no more potent than posaconazole do not require a dose adjustment. No dose adjustment is recommended for patients with mild or moderate renal impairment, mild hepatic impairment, co-administration with a gastric pH modifying agent, mild CYP3A4 inducers, or any other intrinsic or extrinsic factor explored.