Lei Diao (1), Yaming Hang (1), Ahmed A. Othman (2), Devangi Mehta (1), Lakshmi Amaravadi (1), Ivan Nestorov (1), Jonathan Tran (1)
(1) Biogen Idec, Cambridge, MA, (2) AbbVie, North Chicago, IL
Objectives: Daclizumab high-yield process (HYP) is a humanized IgG1 monoclonal antibody specific for CD25, the alpha subunit of the high-affinity interleukin 2 receptor. In registration enabling studies in patients with relapsing forms of multiple sclerosis (RMS), daclizumab HYP demonstrated robust efficacy on clinical endpoints and radiological measures of the disease. This analysis characterized the quantitative relationships between daclizumab HYP exposure and CD25 occupancy on target T cells in blood of RMS patients.
Methods:Population analysis using NONMEM 7.2 was applied to ≥ 7000 observations obtained from 1400 RMS patients participating in the Phase 2 and 3 studies. CD25 saturation was determined using flow cytometry. Saturation was defined as ≤ 1% antigen rich CD4+ T cells staining positive with daclizumab HYP competing antibody. A sequential approach was implemented in which the PK part was fixed utilizing a developed population PK model. Briefly, a two-compartment model adequately described the PK of daclizumab HYP in RMS patients. Clearance was 0.212 L/day and central volume of distribution (Vc) was 3.92 L, scaled by body weight, with exponents of 0.87 and 1.12, respectively. Peripheral volume of distribution was 2.42 L. Absolute bioavailability (100–300 mg) for subcutaneous administration was 88%. Terminal half-life was 21 days. Sampling scheme for CD25 occupancy is sparse mostly once every month except for 19 patients in the intensive PK subgroup in one study (OBSERVE) where the early sampling points included 8h and 24h.
Results: CD25 receptor occupancy by daclizumab HYP in RMS patients was characterized by a sigmoidal inhibitory Emax model. Separate parameters including gamma and IC50 were needed to characterize the saturation following the first dose and the desaturation after treatment cessation. CD25 occupancy upon daclizumab HYP administration is rapid with complete saturation within approximately 7 h post 150 mg SC dose. Maintenance of saturation of CD25 is predicted when daclizumab HYP serum concentration ≥ 5 mg/L while the unoccupied CD25 levels are predicted to return to baseline values when daclizumab HYP serum concentration decreases to approximately ≤ 1 mg/L.
Conclusions:The model described the relationship between daclizumab HYP exposure and the kinetics of CD25 occupancy. At daclizumab HYP exposures determined to be efficacious in clinical trials, the occupancy of CD25 on target T cells was rapid, complete and reversible in parallel with daclizumab HYP clearance from the body.
Reference: PAGE 24 (2015) Abstr 3321 [www.page-meeting.org/?abstract=3321]
Poster: Drug/Disease modeling - Other topics