Population PK-PD analyses of CD25 occupancy, CD56^bright NK cell expansion, and regulatory T cell reduction by daclizumab HYP in subjects with multiple sclerosis.

ABSTRACT:

Aim

Daclizumab high yield process (HYP) is a humanized IgG1 monoclonal antibody that binds to the ?-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.

Methods

Approximately 1400 subjects and 7000 PD measurements for each of three biomarkers [CD25 occupancy, CD56^bright 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 300 mg subcutaneous (s.c.) every 4 weeks.

Results

CD25 occupancy was characterized using a sigmoidal maximum response (E_max ) model. Upon daclizumab HYP treatment, CD25 saturation was rapid with complete saturation occurring after approximately 7 h and maintained when daclizumab HYP serum concentration was ?5 mg l^-1 . After the last 150 mg s.c. dose, unoccupied CD25 returned to baseline levels in approximately 24 weeks, with daclizumab HYP serum concentration approximately ?1 mgl^-1 1L. CD56^bright NK cell expansion was characterized using an indirect response model. Following daclizumab HYP 150 mg s.c. every 4 weeks, expansion plateaus approximately at week 36, at which the average maximum expansion ratio is 5.2. After the last dose, CD56^bright NK cells gradually declined to baseline levels within 24 weeks. Treg reduction was characterized by a sigmoidal E_max model. Average maximum reduction of 60% occurred approximately 4 days post 150 mg s.c. dose. After the last dose, Tregs were projected to return to baseline levels in approximately 20 weeks.

Conclusions

Robust PK-PD models of CD25 occupancy, CD56^bright NK cell expansion and Treg reduction by daclizumab HYP were developed to characterize its key pharmacodynamic effects in the target patient population.

SUBMITTER: Diao L 

PROVIDER: S-EPMC5061794 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature