Population PK-PD analyses of CD25 occupancy, CD56bright NK cell expansion, and regulatory T cell reduction by daclizumab HYP in subjects with multiple sclerosis.

Abstract

Daclizumab high yield process (HYP) is a humanized IgG1 monoclonal antibody that binds to the α-subunit of the interleukin-2 receptor and is being developed for treatment of multiple sclerosis (MS). This manuscript characterized the pharmacokinetic-pharmacodynamic (PK-PD) relationships of daclizumab HYP in subjects with MS. Approximately 1400 subjects and 7000 PD measurements for each of three biomarkers [CD25 occupancy, CD56bright natural killer (NK) cell count, regulatory T cell (Treg) count] from four clinical trials were analyzed using non-linear mixed effects modelling. Evaluated regimens included 150 or 300mg subcutaneous (s.c.) every 4weeks. CD25 occupancy was characterized using a sigmoidal maximum response (Emax ) model. Upon daclizumab HYP treatment, CD25 saturation was rapid with complete saturation occurring after approximately 7h and maintained when daclizumab HYP serum concentration was ≥5mgl-1 . After the last 150mg s.c. dose, unoccupied CD25 returned to baseline levels in approximately 24weeks, with daclizumab HYP serum concentration approximately ≤1mgl-1 1L. CD56bright NK cell expansion was characterized using an indirect response model. Following daclizumab HYP 150mg s.c. every 4weeks, expansion plateaus approximately at week 36, at which the average maximum expansion ratio is 5.2. After the last dose, CD56bright NK cells gradually declined to baseline levels within 24weeks. Treg reduction was characterized by a sigmoidal Emax model. Average maximum reduction of 60% occurred approximately 4days post 150mg s.c. dose. After the last dose, Tregs were projected to return to baseline levels in approximately 20weeks. Robust PK-PD models of CD25 occupancy, CD56bright NK cell expansion and Treg reduction by daclizumab HYP were developed to characterize its key pharmacodynamic effects in the target patient population.