Candice Jamois, David C. Turner, Leonid Gibiansky, Feifei Li, Jean-Francois Menuet, Leonardo Roque Pereira, Linda Lundberg, Elena Guerini, David J. Carlile, James Relf, Michael C. Wei, Antonia Kwan, Nicolas Frey, Susan Grange
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引用次数: 0
Abstract
The recent surge in T-cell-engaging and chimeric antigen receptor (CAR) T-cell therapies is changing the landscape of cancer therapy. Cytokine release syndrome (CRS) is a systemic inflammatory response syndrome that is a well-known complication of these therapies, of which interleukin-6 (IL-6) is a key mediator. Tocilizumab, an IL-6 receptor (IL-6R) antagonist, is approved for the management of CAR T-cell therapy-induced CRS in adults and in pediatric patients aged ≥ 2 years old. However, the approved dosing schedule was not based on IL-6R occupancy and may not be the most suitable schedule for T-cell-engaging therapies such as bispecific antibodies (bsAb) due to key differences in the levels of released IL-6, the clinical symptomatology of CRS, and the pharmacology of tocilizumab across settings. In this study, we adapted a previously developed tocilizumab and soluble IL-6R (sIL-6R) population pharmacokinetic model to describe and predict tocilizumab concentrations and sIL-6R occupancy over time in patients with anti-CD20 bsAb-induced CRS following tocilizumab dosing. Using this model, which incorporates target binding and receptor occupancy, we propose a new tocilizumab dosing regimen that is based on quantitative clinical pharmacology, cytokine analyses, and clinical practice patterns in patients with relapsed/refractory B-cell non-Hodgkin's lymphoma (R/R B-NHL) treated with the anti-CD20 bsAb mosunetuzumab or glofitamab. This schedule (up to two 8 mg/kg intravenous tocilizumab doses per CRS event at least 8 hours apart and a maximum of three doses in 6 weeks) can be used to effectively manage acute CRS induced by anti-CD20 bsAb in patients with R/R B-NHL.
期刊介绍:
Clinical Pharmacology & Therapeutics (CPT) is the authoritative cross-disciplinary journal in experimental and clinical medicine devoted to publishing advances in the nature, action, efficacy, and evaluation of therapeutics. CPT welcomes original Articles in the emerging areas of translational, predictive and personalized medicine; new therapeutic modalities including gene and cell therapies; pharmacogenomics, proteomics and metabolomics; bioinformation and applied systems biology complementing areas of pharmacokinetics and pharmacodynamics, human investigation and clinical trials, pharmacovigilence, pharmacoepidemiology, pharmacometrics, and population pharmacology.