Dose selection of siltuximab for multicentric Castleman's disease.

Abstract

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.

• Authors: Christina L Mayer, Lanyi Xie, Rajesh Bandekar, Ming Qi, Helgi van de Velde, Manjula Reddy, Xiang Qin, Hugh M Davis, Thomas A Puchalski
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 75 Issue 5 Pg. 1037-45 (May 2015) ISSN: 1432-0843 [Electronic] Germany
• PMID: 25784388 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• siltuximab

Topics

• Aged
• Antibodies, Monoclonal (administration & dosage, blood, pharmacokinetics)
• Antineoplastic Agents (administration & dosage, blood, pharmacokinetics)
• Castleman Disease (blood, drug therapy, metabolism)
• Dose-Response Relationship, Drug
• Humans
• Infusions, Intravenous
• Middle Aged
• Models, Biological
• Randomized Controlled Trials as Topic