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Dose selection of siltuximab for multicentric Castleman’s disease

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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.

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Acknowledgments

This study was funded and supported by Janssen Research & Development, LLC. The authors thank Robert Achenbach and Gianna Paone of Janssen Scientific Affairs, LLC, for editorial and submission support.

Conflict of interest

All authors are or were employees of Janssen Research & Development, LLC, at the time of the study and own(ed) stock in Johnson & Johnson.

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Authors and Affiliations

  1. Janssen Research & Development, LLC, Spring House, PA, USA

    Christina L. Mayer, Lanyi Xie, Rajesh Bandekar, Ming Qi, Manjula Reddy, Xiang Qin, Hugh M. Davis & Thomas A. Puchalski

  2. Janssen Research & Development, Beerse, Belgium

    Helgi van de Velde

  3. Biologics Clinical Pharmacology, Janssen Research & Development, LLC, 1400 McKean Road, P.O. Box 776, Spring House, PA, 19477, USA

    Thomas A. Puchalski

Authors
  1. Christina L. Mayer
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  2. Lanyi Xie
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  3. Rajesh Bandekar
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  4. Ming Qi
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  7. Xiang Qin
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  8. Hugh M. Davis
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  9. Thomas A. Puchalski
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Correspondence to Thomas A. Puchalski.

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Mayer, C.L., Xie, L., Bandekar, R. et al. Dose selection of siltuximab for multicentric Castleman’s disease. Cancer Chemother Pharmacol 75, 1037–1045 (2015). https://doi.org/10.1007/s00280-015-2720-0

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  • DOI: https://doi.org/10.1007/s00280-015-2720-0

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