Abstract
Purpose
To characterize the effects of disease type and clinical characteristics on the pharmacokinetics of siltuximab, an IL-6 inhibiting monoclonal antibody.
Methods
Siltuximab pharmacokinetic data were combined from seven phase I/II clinical trials. A population pharmacokinetic model was developed to characterize changes in siltuximab disposition with disease type, albumin, liver and renal function, and patient demographics.
Results
A total of 7761 concentrations from 460 participants were used in the study. The data were well described by a two-compartment model. Castleman’s disease, healthy volunteer status, albumin, and ALT were independent predictors of clearance. Monte Carlo simulations of the final model for an 11 mg/kg dose resulted in a longer median half-life for healthy volunteers (24.5 days) as compared to Castleman’s disease (19.1 days) and other tumor types (22.2 days). Clearance varied 1.8-fold over the range of albumin values seen in the study (1.5–5.2 g/dL), while ALT resulted in minimal changes in clearance.
Conclusions
Albumin and disease state are important factors for siltuximab disposition and will likely need to be considered for dosing in future therapeutic applications.
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Acknowledgements
The clinical trials presented in the study were funded by Janssen Pharmaceuticals. Funding support was provided by a Research in Pediatric and Developmental Pharmacology NIH grant (1U54HD090259-01, Dr. Capparelli).
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Dr. Capparelli serves on the data safety and monitoring board for Cempra Pharmaceuticals and Celltrion. Dr. Nikanjam and Dr. Yang have no potential conflicts of interest.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
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Nikanjam, M., Yang, J. & Capparelli, E.V. Population pharmacokinetics of siltuximab: impact of disease state. Cancer Chemother Pharmacol 84, 993–1001 (2019). https://doi.org/10.1007/s00280-019-03939-7
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DOI: https://doi.org/10.1007/s00280-019-03939-7