title: Blockade of the High-Affinity Interleukin-2 Receptors with Daclizumab High-Yield Process: Pharmacokinetic/Pharmacodynamic Analysis of Single- and Multiple-Dose Phase I Trials.
abstract: OBJECTIVE
  Daclizumab high-yield process (DAC HYP) is a humanized monoclonal antibody that selectively blocks the α-subunit (CD25) of the high-affinity interleukin-2 receptors, and has shown robust efficacy as a treatment for multiple sclerosis (MS). This work quantitatively characterized the relationship between DAC HYP serum concentrations and saturation of CD25 expressed on antigen-rich target T cells in blood.
  
  
  METHODS
  Serial pharmacokinetic and 968 CD25 measurements from three double-blind, randomized, placebo-controlled, phase I studies of DAC HYP (50-300 mg subcutaneous and 200-400 mg intravenous doses or placebo) in healthy volunteers (n = 95) were analyzed using nonlinear mixed-effects modeling. CD25 occupancy was determined using flow cytometry and a fluorescently-labeled DAC HYP-competing antibody.
  
  
  RESULTS
  CD25 occupancy was described using a direct inhibitory sigmoidal maximum effect (E max) model (where DAC HYP fully inhibited CD25 labeling with competing antibody). Two IC50 (serum concentration corresponding to 50 % of maximal inhibition) parameters were used to describe rapid CD25 saturation at initiation of dosing and apparently slower desaturation during DAC HYP washout. Parameter estimates (95 % bootstrap confidence intervals) were: baseline CD25 labeling, 47 % (45-48); DAC HYP IC50(saturation), 0.023 µg/mL (0.005-0.073); IC50(desaturation) 0.86 µg/mL (0.74-0.98); Hill coefficient 5.6 (4.3-6.8).
  
  
  CONCLUSIONS
  Based on the developed model, the 150 mg monthly subcutaneous regimen of DAC HYP in subjects with MS is predicted to saturate CD25 on target effector T cells within a few hours of dosing and maintain CD25 saturation during the entire dosing interval. Free CD25 levels return to baseline within 4-6 months of the last DAC HYP dose.
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie, 1 North Waukegan Road, North Chicago, IL, USA.
authors.forename: Mukul
authors.initials: M
authors.lastname: Minocha
authors.affiliation: Clinical Pharmacology, Biogen, Cambridge, MA, USA.
authors.forename: Jonathan Q
authors.initials: JQ
authors.lastname: Tran
authors.affiliation: AbbVie Biotherapeutics, Redwood City, CA, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Sheridan
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie, 1 North Waukegan Road, North Chicago, IL, USA. ahmed.othman@abbvie.com.|Faculty of Pharmacy, Cairo University, Cairo, Egypt. ahmed.othman@abbvie.com.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Othman
mesh_terms: D061605:Administration, Intravenous; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000077561:Daclizumab; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage*; D053645:Interleukin-2 Receptor alpha Subunit / Q000097:blood; D008954:Models, Biological; D017711:Nonlinear Dynamics; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C508017:IL2RA protein, human; D007074:Immunoglobulin G; D053645:Interleukin-2 Receptor alpha Subunit; D015375:Receptors, Interleukin-2; D000077561:Daclizumab