Dose selection of siltuximab for multicentric Castleman's disease

Cancer Chemotherapy and Pharmacology
Christina L MayerThomas A Puchalski

Abstract

Siltuximab is a monoclonal antibody that binds to interleukin (IL)-6 with high affinity and specificity; C-reactive protein (CRP) is an acute-phase protein induced by IL-6. CRP suppression is an indirect measurement of IL-6 activity. Here, modeling and simulation of the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between siltuximab and CRP were used to support dose selection for multicentric Castleman's disease (CD). PK/PD modeling was applied to explore the relationship between siltuximab PK and CRP suppression following intravenous siltuximab infusion in 47 patients with B cell non-Hodgkin's lymphoma (n = 17), multiple myeloma (n = 13), or CD (n = 17). Siltuximab was administered as 2.8, 5.5, or 11 mg/kg q2wks, 11 mg/kg q3wks, or 5.5 mg/kg weekly. Simulations of studied or hypothetical siltuximab dosage regimens (15 mg/kg q4wks) were also performed to evaluate maintenance of CRP suppression below the cutoff value of 1 mg/L. A two-compartment PK model and an inhibitory indirect response PD model adequately described the serum siltuximab and CRP concentration-time profiles simultaneously. PD parameter estimates were physiologically plausible. For all disease types, simulations showed that 11 mg/kg q3wks or 15 mg/kg q...Continue Reading

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Citations

Sep 24, 2015·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Katherine A Lyseng-Williamson
Dec 5, 2015·Immunotherapy·David C Fajgenbaum, Razelle Kurzrock
Apr 5, 2017·CPT: Pharmacometrics & Systems Pharmacology·A M Stein, R Ramakrishna
Nov 30, 2018·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Ali Berkant AvciGerd Rüdiger Burmester

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