Itacitinib Population Pharmacokinetics and Exposure‐Response in Patients With Acute Graft‐Versus‐Host Disease

Abstract

AbstractThis article presents the population pharmacokinetic (PopPK) analysis and exposure‐response analyses for the primary efficacy end point—acute graft‐versus‐host disease (aGVHD) day 28 response—and select safety measures (incidence of thrombocytopenia, hypertriglyceridemia, and cytomegalovirus infection) from a phase 3 randomized, double‐blind study comparing itacitinib plus corticosteroids versus placebo plus corticosteroids for the treatment of aGVHD. The PopPK data set contained sparse data from patients with aGVHD and select enriched data from healthy volunteers. The structural model was a 2‐compartment model with first‐order elimination and dose‐dependent nonlinear absorption with dual first‐order absorption pathways with lag times. Strong cytochrome P450 (CYP) 3A inhibitor coadministration, moderate renal impairment, and participant population (healthy volunteers vs patients with aGVHD) were covariates on apparent clearance. Participant population was also a covariate on apparent intercompartmental clearance and lag time of the secondary absorption compartment. Apparent clearance decreased 42% with coadministration of strong CYP3A inhibitors. Simulations supported the following dose reductions with concomitant use of a strong CYP3A inhibitor: 300 mg once daily to 200 mg once daily, 400 mg once daily to 300 mg once daily, and 600 mg once daily to 400 mg once daily. No dose adjustment is recommended for any other covariate based on the magnitude of impact when they were retained in the model. The exposure‐response relationship was characterized between itacitinib exposure and probability of aGVHD day 28 response using a linear logistic regression model. Both itacitinib exposure and aGVHD risk status were significant predictors of response. There was no relationship between itacitinib exposure and thrombocytopenia, hypertriglyceridemia, or cytomegalovirus infection.