| Autor: |
Hartmann S; Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida, Orlando, FL, USA., Biliouris K; Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida, Orlando, FL, USA., Naik H; Biogen Inc., 225 Binney Street, Cambridge, MA, 02142, USA. himanshu.naik@biogen.com., Rabah D; Biogen Inc., 225 Binney Street, Cambridge, MA, 02142, USA., Stevenson L; Immunologix Laboratories, Tampa, FL, USA., Shen C; Biogen Inc., 225 Binney Street, Cambridge, MA, 02142, USA., Nestorov IA; Biogen Inc., 225 Binney Street, Cambridge, MA, 02142, USA., Lesko LJ; Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida, Orlando, FL, USA., Trame MN; Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida, Orlando, FL, USA. |
| Abstrakt: |
A population pharmacokinetic/pharmacodynamic (popPK/PD) model for BIIB059 (anti-blood dendritic cell antigen 2 [anti-BDCA2]), a humanized immunoglobulin G1 monoclonal antibody currently under development for the treatment of SLE and CLE, is presented. BIIB059 binds BDCA2, a plasmacytoid dendritic cell (pDC)-specific receptor that inhibits the production of IFN-I and other inflammatory mediators when ligated. Phase 1 PK and PD data of healthy adult volunteers (HV, n = 87) and SLE subjects (n = 22) were utilized for the development of the popPK/PD model. The data included single and multiple dosing of intravenous and subcutaneous BIIB059. BDCA2 internalization (PD marker) was measured for all subjects by monitoring reduction of BDCA2 on pDC cell surface and used for development of the popPD model. A two-compartment popPK model with linear plus non-linear elimination was found to best describe BIIB059 PK. BDCA2 levels were best captured using an indirect response model with stimulation of the elimination of BDCA2. Clearance in SLE subjects was 25% higher compared to HV (6.87 vs 5.52 mL/h). Bodyweight was identified as only other covariate on clearance and central volume. The estimates of EC 50 and E max were 0.35 μg/mL and 8.92, respectively. No difference in EC 50 and E max was observed between SLE and HV. The popPK/PD model described the data accurately, as evaluated by pcVPCs and bootstrap. The presented popPK/PD model for BIIB059 provides valuable insight into the dynamics and dose-response relationship of BIIB059 for the treatment of SLE and CLE and was used to guide dose selection for the Phase 2 clinical study (NCT02847598). |
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