Lei Diao1, Yaming Hang2, Ahmed A Othman3,4, Devangi Mehta2, Lakshmi Amaravadi5, Ivan Nestorov2, Jonathan Q Tran6. 1. Janssen China R&D, Clinical Pharmacology, Shanghai, China. leidiao@hotmail.com. 2. Biogen, Cambridge, MA, 02142. 3. AbbVie Clinical Pharmacology and Pharmacometrics, North Chicago, IL, 60064, USA. 4. Faculty of Pharmacy, Cairo University, Cairo, Egypt. 5. Sanofi-Genzyme, Cambridge, MA, 02142. 6. Receptos, a wholly owned subsidiary of Celgene, San Diego, CA, 92121, USA.
Abstract
AIM: 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. METHODS: 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 300 mg subcutaneous (s.c.) every 4 weeks. RESULTS: 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 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. CD56bright 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, CD56bright NK cells gradually declined to baseline levels within 24 weeks. Treg reduction was characterized by a sigmoidal Emax 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, CD56bright NK cell expansion and Treg reduction by daclizumab HYP were developed to characterize its key pharmacodynamic effects in the target patient population.
AIM: 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. METHODS: 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 300 mg subcutaneous (s.c.) every 4 weeks. RESULTS: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 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. CD56bright 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, CD56bright NK cells gradually declined to baseline levels within 24 weeks. Treg reduction was characterized by a sigmoidal Emax 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, CD56bright NK cell expansion and Treg reduction by daclizumab HYP were developed to characterize its key pharmacodynamic effects in the target patient population.
Authors: David J Huss; Devangi S Mehta; Akanksha Sharma; Xiaojun You; Katherine A Riester; James P Sheridan; Lakshmi S Amaravadi; Jacob S Elkins; Jason D Fontenot Journal: J Immunol Date: 2015-01-01 Impact factor: 5.422
Authors: Daniel Wynn; Michael Kaufman; Xavier Montalban; Timothy Vollmer; Jack Simon; Jacob Elkins; Gilmore O'Neill; Lauri Neyer; James Sheridan; Chungchi Wang; Alice Fong; John W Rose Journal: Lancet Neurol Date: 2010-02-15 Impact factor: 44.182
Authors: J Elkins; J Sheridan; L Amaravadi; K Riester; K Selmaj; B Bielekova; E Parr; G Giovannoni Journal: Neurol Neuroimmunol Neuroinflamm Date: 2015-01-22
Authors: Ludwig Kappos; Stanley Cohan; Douglas L Arnold; Randy R Robinson; Joan Holman; Sami Fam; Becky Parks; Shan Xiao; Wanda Castro-Borrero Journal: Ther Adv Neurol Disord Date: 2021-02-26 Impact factor: 6.570