Alemtuzumab Exposure and T Lymphocyte Depletion: A Population Pharmacokinetic-Pharmacodynamic Model of Alemtuzumab Induction Therapy for Kidney Transplantation

Alemtuzumab is a T cell-depleting monoclonal antibody that is used for the prevention of kidney transplant rejection. The duration of lymphodepletion after the current standard induction therapy dose is likely longer than necessary, resulting in prolonged T cell lymphopenia with the associated risk of infections. Here, the interplay between alemtuzumab exposure and T cell dynamics was quantitatively evaluated, and the influence of different doses on T cell recovery was investigated. A population pharmacokinetic-pharmacodynamic model describing the interplay between 30 mg alemtuzumab induction therapy and T cell dynamics in kidney transplantation was developed using NONMEM, using pharmacodynamic data from the Triton study (NCT02057965). The developed model was used to perform an exposure-response analysis and investigate dose optimization with model-derived simulations. In total, 418 peripheral blood T cell measurements from 61 adult kidney transplant recipients were included for model development. A single-compartment turnover E_max model with a first-order T cell influx with feedback and a first-order T cell efflux with parallel alemtuzumab-stimulated T cell removal best described the data. Higher alemtuzumab exposure was associated with lower individual-predicted T cells 4 weeks after administration and longer T cell recovery (> 200 cells/μL). In the simulations, a fixed dose of 15 mg improved median recovery times by 19 days as compared to the standard 30 mg dose without influencing early T cell depletion. A population pharmacokinetic-pharmacodynamic model adequately described T cell dynamics after alemtuzumab induction therapy in kidney transplant recipients. This model can be used to inform future dose-optimization studies of alemtuzumab in different clinical settings.