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

by Selleckchem | Jul 01 2023

This 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.

Comments:

This article describes a population pharmacokinetic (PopPK) analysis and exposure-response analysis conducted in a phase 3 randomized, double-blind study. The study compared the efficacy and safety of itacitinib plus corticosteroids versus placebo plus corticosteroids for the treatment of acute graft-versus-host disease (aGVHD).

The PopPK analysis utilized sparse data from patients with aGVHD and enriched data from healthy volunteers. A 2-compartment model with first-order elimination and dose-dependent nonlinear absorption, including dual first-order absorption pathways with lag times, was used as the structural model. Several covariates were considered, including strong cytochrome P450 (CYP) 3A inhibitor coadministration, moderate renal impairment, and participant population (healthy volunteers vs patients with aGVHD). Apparent clearance was affected by these covariates, with a 42% decrease observed with coadministration of strong CYP3A inhibitors. The participant population was also found to impact apparent intercompartmental clearance and lag time of the secondary absorption compartment.

Based on the simulations, dose reductions were recommended when itacitinib was coadministered with strong CYP3A inhibitors. The suggested dose reductions were as follows: 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 was recommended for other covariates, as their impact on the model was not significant.

The exposure-response relationship between itacitinib exposure and the probability of aGVHD day 28 response was assessed using a linear logistic regression model. Both itacitinib exposure and aGVHD risk status were identified as significant predictors of response. However, no relationship was observed between itacitinib exposure and the occurrence of thrombocytopenia, hypertriglyceridemia, or cytomegalovirus infection.

Overall, this study provides insights into the pharmacokinetics of itacitinib in patients with aGVHD and the relationship between drug exposure and treatment response, as well as safety measures. The findings support dose adjustments when itacitinib is coadministered with strong CYP3A inhibitors to optimize treatment outcomes and minimize potential adverse effects.