title: Dose selection of siltuximab for multicentric Castleman's disease.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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 q4wks would reduce serum CRP to below 1 mg/L after the second dose and throughout the treatment period.
  
  
  CONCLUSIONS
  PK/PD modeling was used to select doses for further development of siltuximab in multicentric CD. The dosing recommendation was also supported by the observed efficacy dose-response relationship. CRP suppression in the subsequent randomized multicentric CD study was in agreement with the modeling predictions.
authors.affiliation: Janssen Research & Development, LLC, Spring House, PA, USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Mayer
authors.forename: Lanyi
authors.initials: L
authors.lastname: Xie
authors.forename: Rajesh
authors.initials: R
authors.lastname: Bandekar
authors.forename: Ming
authors.initials: M
authors.lastname: Qi
authors.forename: Helgi
authors.initials: H
authors.lastname: van de Velde
authors.forename: Manjula
authors.initials: M
authors.lastname: Reddy
authors.forename: Xiang
authors.initials: X
authors.lastname: Qin
authors.forename: Hugh M
authors.initials: HM
authors.lastname: Davis
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Puchalski
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D005871:Castleman Disease / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D008954:Models, Biological; D016032:Randomized Controlled Trials as Topic
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C504234:siltuximab