Kumar Kandadi (1), Ivan Nestorov (1), Geoffrey Kuesters (2), Meena Subramanyam (2), Tatiana Plavina (2)
(1) Systems Pharmacology, Biogen, Cambridge, MA, USA. (2) Translational Sciences, Biogen, Cambridge, MA, USA.
Objectives: Natalizumab is a first-in-class, humanized anti-α4 integrin antibody used to treat MS. Currently, no robust quantitative models describe the PK of natalizumab and the natalizumab concentration-α4 integrin saturation relationship. The objective of this analysis is to develop a population PK and PD model to characterize natalizumab PK and α4 integrin saturation (PD) across MS subjects with intravenous (IV) natalizumab administration.
Methods: The natalizumab serum PK and α4 integrin saturation PD data were obtained across 2 phase 2, 3 phase 3, and 5 postmarketing clinical studies. In total, 12788 serum and 4917 α4 integrin samples from 12788 patients were included in the population analysis. PK and PD models were developed sequentially using NONMEM (version 7.3). Diagnostics plots and various predictive check procedures were used for model evaluation.
Results: Natalizumab PK was best described by a 2-compartmental model with linear and Michaelis-Menten elimination. Based on the model, the median (95% confidence interval) linear clearance (CL) is 6.21 mL/h (5.60-6.70), median volume of distribution at steady state (Vss) is 5.58 L (5.27-5.92), and terminal elimination half-life (t1/2,β) is 26.8 days. 90% of steady state concentrations were expected to be reached by 5-7 months for an individual dosed with 300 mg Q4W (every 4 weeks) IV natalizumab. Covariate analysis showed that CL, V1 (central volume of distribution) increased as body weight increased. CL was higher in subjects who were administered with phase 2B formulations relative to commercial formulations and in those who developed binding antibodies to natalizumab. The relationship between natalizumab concentration and α4 integrin saturation was best described by a direct response model with a sigmoidal effect on α4 integrin saturation mediated by an Emax relationship with natalizumab concentrations. The model-estimated Emax and EC50 were 83.8% and 2.51 mg/L, respectively. The magnitude of PD response as measured by Emax and Hill coefficient was affected by administered natalizumab formulation and subject age.
Conclusions: The population PK-PD model adequately characterized natalizumab PK-PD in MS subjects. The nonspecific disposition component (CL, VSS) estimates were consistent with results obtained for other IgG monoclonal antibodies [1]. The PK-PD covariates, although statistically significant, are not expected to have any clinical impact at the approved clinical dosing regimen (300 mg Q4W).
References:
[1] Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(10):633-59.
Reference: PAGE 25 (2016) Abstr 5988 [www.page-meeting.org/?abstract=5988]
Poster: Drug/Disease modeling - CNS