Mina Nikanjam1,2, Jin Yang3, Edmund V Capparelli4. 1. Center for Personalized Cancer Therapy and Division of Hematology and Oncology, UC San Diego Moores Cancer Center, San Diego, CA, USA. mnikanjam@ucsd.edu. 2. University of California San Diego, 3855 Health Sciences Drive, MC 0658, La Jolla, CA, 92037, USA. mnikanjam@ucsd.edu. 3. Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, San Diego, CA, USA. 4. Division of Host-Microbe Systems and Therapeutics, University of California San Diego, San Diego, CA, USA.
Abstract
PURPOSE: To characterize the effects of disease type and clinical characteristics on the pharmacokinetics of siltuximab, an IL-6 inhibiting monoclonal antibody. METHODS: Siltuximab pharmacokinetic data were combined from seven phase I/II clinical trials. A population pharmacokinetic model was developed to characterize changes in siltuximab disposition with disease type, albumin, liver and renal function, and patient demographics. RESULTS: A total of 7761 concentrations from 460 participants were used in the study. The data were well described by a two-compartment model. Castleman's disease, healthy volunteer status, albumin, and ALT were independent predictors of clearance. Monte Carlo simulations of the final model for an 11 mg/kg dose resulted in a longer median half-life for healthy volunteers (24.5 days) as compared to Castleman's disease (19.1 days) and other tumor types (22.2 days). Clearance varied 1.8-fold over the range of albumin values seen in the study (1.5-5.2 g/dL), while ALT resulted in minimal changes in clearance. CONCLUSIONS: Albumin and disease state are important factors for siltuximab disposition and will likely need to be considered for dosing in future therapeutic applications.
PURPOSE: To characterize the effects of disease type and clinical characteristics on the pharmacokinetics of siltuximab, an IL-6 inhibiting monoclonal antibody. METHODS:Siltuximab pharmacokinetic data were combined from seven phase I/II clinical trials. A population pharmacokinetic model was developed to characterize changes in siltuximab disposition with disease type, albumin, liver and renal function, and patient demographics. RESULTS: A total of 7761 concentrations from 460 participants were used in the study. The data were well described by a two-compartment model. Castleman's disease, healthy volunteer status, albumin, and ALT were independent predictors of clearance. Monte Carlo simulations of the final model for an 11 mg/kg dose resulted in a longer median half-life for healthy volunteers (24.5 days) as compared to Castleman's disease (19.1 days) and other tumor types (22.2 days). Clearance varied 1.8-fold over the range of albumin values seen in the study (1.5-5.2 g/dL), while ALT resulted in minimal changes in clearance. CONCLUSIONS:Albumin and disease state are important factors for siltuximab disposition and will likely need to be considered for dosing in future therapeutic applications.
Entities:
Keywords:
Castleman’s disease; IL-6; Oncology; Population pharmacokinetics; Siltuximab
Authors: N Nishimoto; M Sasai; Y Shima; M Nakagawa; T Matsumoto; T Shirai; T Kishimoto; K Yoshizaki Journal: Blood Date: 2000-01-01 Impact factor: 22.113
Authors: J-F Rossi; S Négrier; N D James; I Kocak; R Hawkins; H Davis; U Prabhakar; X Qin; P Mulders; B Berns Journal: Br J Cancer Date: 2010-08-31 Impact factor: 7.640