Dose selection of siltuximab for multicentric Castleman’s disease

• Published in: Cancer chemotherapy and pharmacology Vol. 75; no. 5; pp. 1037 - 1045
• Main Authors: Mayer, Christina L., Xie, Lanyi, Bandekar, Rajesh, Qi, Ming, van de Velde, Helgi, Reddy, Manjula, Qin, Xiang, Davis, Hugh M., Puchalski, Thomas A.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-05-2015; Springer Nature B.V
• Subjects: Aged; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - blood; Antibodies, Monoclonal - pharmacokinetics; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Cancer Research; Castleman Disease - blood; Castleman Disease - drug therapy; Castleman Disease - metabolism; Dose-Response Relationship, Drug; Humans; Infusions, Intravenous; Medicine; Medicine & Public Health; Middle Aged; Models, Biological; Oncology; Original Article; Pharmacology/Toxicology; Randomized Controlled Trials as Topic; Siltuximab; Pharmacodynamics; Pharmacokinetics; Modeling; Dose selection
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-015-2720-0

Purpose
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.