Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics

Golay, Joseé; Semenzato, Gianpietro; Rambaldi, Alessandro; Foà, Robin; Gaïdano, Gianluca; Gamba, Enrica; Pane, Fabrizio; Pinto, Antonello; Specchia, Giorgina; Zaja, Francesco; Regazzi, Mario

doi:10.4161/mabs.26008

Cited by 115 publications

(96 citation statements)

References 103 publications

(161 reference statements)

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“…The consequence, in the case of CD20 mAbs, is that opsonized cells are subject to trogocytosis; ironically, the excess CD20 mAb remaining in the circulation actually helps the circulating malignant B cells "escape" by promoting trogocytosis of mAb/ CD20 complexes . The pharmacokinetics and pharmacodynamics of RTX and OFA have been comprehensively studied (Berinstein et al, 1998;Coiffier et al, 2010;Golay et al, 2013b). At high doses, RTX (and OFA) can persist in the circulation for several months, and we found that CD20 levels on circulating CLL cells remained depressed over extended periods for up to 1 month or longer after infusions of large doses of these mAbs Beurskens et al, 2012).…”

Section: Quantitative Considerationsmentioning

confidence: 84%

“…We propose that a more reasonable and generally applicable dosing paradigm would be to periodically treat cancer patients with much smaller mAb doses, either intravenously at 30-40 mg or subcutaneously at 50-60 mg to compensate for less efficient absorption (Golay et al, 2013b), and to repeat these doses approximately three times per week Aue et al, 2010;Zent et al, 2014). The hypothesis is that each infusion will promote killing of a fraction of the tumor cells, and that trogocytosis will be minimized.…”

Section: Concluding Remarks: the Way Forwardmentioning

confidence: 99%

“…Indeed, although the pharmacokinetics and pharmacodynamics of RTX and of OFA for high mAb doses have been intensively studied (Berinstein et al, 1998;Coiffier et al, 2010;Golay et al, 2013b), several lines of evidence indicate that, particularly for chronic lymphocytic leukemia (CLL), the most effective doses and their timing require critical re-evaluation Baig et al, 2014;Zent et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Analyses of CD20 Monoclonal Antibody–Mediated Tumor Cell Killing Mechanisms: Rational Design of Dosing Strategies

Taylor

Lindorfer

2014

Mol Pharmacol

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Since approval of rituximab for treatment of B cell non-Hodgkin lymphoma, development of monoclonal antibodies (mAbs) for cancer treatment and elucidation of their cytotoxic mechanisms have been subject to intense investigations. Compelling evidence indicates that rituximab and another CD20 mAb, ofatumumab, must use the body's cellular and humoral immune effector functions to kill malignant cells. Other U.S. Food and Drug Administration-approved mAbs, including obinutuzumab, cetuximab, and trastuzumab, require, in part, these effector mechanisms to eliminate tumor cells. Although gram quantities of mAbs can be administered to patients, our investigations of CD20 mAb-based therapies for chronic lymphocytic leukemia (CLL), including correlative measurements in clinical trials and studies with primary cells and cell lines, indicate that effector mechanisms necessary for mAb activity can be saturated or exhausted if tumor burdens are high, thus substantially compromising the efficacy of high-dose mAb therapy. Under these conditions, another reaction (trogocytosis) predominates in which bound CD20 mAb and CD20 are removed from targeted cells by effector cells that express Fcg receptors, thereby allowing malignant cells to escape unharmed and continue to promote disease pathology. To address this problem, we propose that a low-dose strategy, based on administering 30-50 mg of CD20 mAb three times per week, may be far more effective for CLL than standard dosing because it will minimize effector function saturation and reduce trogocytosis. This approach may have general applicability to other mAbs that use immune effector functions, and could be formulated into a subcutaneous treatment strategy that would be more accessible and possibly more efficacious for patients.

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Section: Quantitative Considerationsmentioning

confidence: 84%

Section: Concluding Remarks: the Way Forwardmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Analyses of CD20 Monoclonal Antibody–Mediated Tumor Cell Killing Mechanisms: Rational Design of Dosing Strategies

Taylor

Lindorfer

2014

Mol Pharmacol

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“…Rituximab PK was satisfactorily described using a 2-compartment model as in previous studies. 13,14,25,[29][30][31] We observed a decrease in exposure to rituximab with increasing TMTV 0 . Similarly, rituximab serum levels were previously shown to correlate inversely with tumor bulk at baseline in low-grade lymphoma.…”

Section: Discussionmentioning

confidence: 99%

Rituximab exposure is influenced by baseline metabolic tumor volume and predicts outcome of DLBCL patients: a Lymphoma Study Association report

Tout

Casasnovas

Meignan

et al. 2017

Blood

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Key Points• Rituximab exposure decreased as metabolic tumor volume increased, and correlated with metabolic response and survival.• Rituximab dose could be individualized according to metabolic tumor volume to achieve optimal exposure and therefore optimal response.High variability in patient outcome after rituximab-based treatment is partly explained by rituximab concentrations, and pharmacokinetic (PK) variability could be influenced by tumor burden. We aimed at quantifying the influence of baseline total metabolic tumor volume (TMTV 0 ) on rituximab PK and of TMTV 0 and rituximab exposure on outcome in patients with diffuse large B-cell lymphoma (DLBCL). TMTV 0 was measured by 18 F-fluorodeoxyglucosepositron emission tomography-computed tomography in 108 previously untreated DLBCL patients who received four 375 mg/m 2 rituximab infusions every 2 weeks in combination with chemotherapy in 2 prospective trials. A 2-compartment population model allowed describing rituximab PK and calculating rituximab exposure (area under the concentration-time curve; AUC). The association of TMTV 0 and AUC with metabolic response after 4 cycles, as well as progression-free survival (PFS) and overall survival (OS), was assessed using logistic regression and Cox models, respectively. Cutoff values for patient outcome were determined using receiver operating characteristic curve analysis. Exposure to rituximab decreased as TMTV 0 increased (R 2 5 0.41, P < .0001). A high AUC in cycle 1 ( ‡9400 mg 3 h per liter) was associated with better response (odds ratio, 5.56; P 5 .0006) and longer PFS (hazard ratio [HR], 0.38; P 5 .011) and OS (HR, 0.17; P 5 .001).A nomogram for rituximab dose needed to obtain optimal AUC according to TMTV 0 was constructed, and the 375 mg/m 2 classical dose would be suitable for patients with TMTV 0 <281 cm 3 . In summary, rituximab exposure is influenced by TMTV 0 and correlates with response and outcome of DLBCL patients. Dose individualization according to TMTV 0 should be evaluated in prospective studies. These studies were registered at www.clinicaltrials.gov as #NCT00498043 and

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“…These mechanisms depend on the Fc portion of the antibody binding to the Fc gamma receptors (FcγRs) on immune cells. Other mechanisms are aggregation of targeted cells or direct cell death through CD20 signaling [Golay et al 2013].…”

Section: Pharmacology Of Rituximabmentioning

confidence: 99%

An update on the evidence for the efficacy and safety of rituximab in the management of neuromyelitis optica

Collongues

Seze

2016

Ther Adv Neurol Disord

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Neuromyelitis optica spectrum disorders (NMOSDs) is a new concept which includes classical neuromyelitis optica (NMO) and partial forms of NMO such as recurrent optic neuritis with positive aquaporin-4 antibodies (AQP4) or brainstem symptoms (intractable hiccups or vomiting). This disease is clearly distinguished from multiple sclerosis (MS) and the therapeutic approach is clearly different. Rituximab is actually considered to be one of the most efficient treatments of NMOSD, even if class I studies are clearly lacking. In the present review, we describe the state of the art about rituximab treatment in NMOSD, including adults and children, plus its efficacy and tolerance and we also underline the questions that should be addressed in the near future.

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Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics

Cited by 115 publications

References 103 publications

Analyses of CD20 Monoclonal Antibody–Mediated Tumor Cell Killing Mechanisms: Rational Design of Dosing Strategies

Analyses of CD20 Monoclonal Antibody–Mediated Tumor Cell Killing Mechanisms: Rational Design of Dosing Strategies

Rituximab exposure is influenced by baseline metabolic tumor volume and predicts outcome of DLBCL patients: a Lymphoma Study Association report

An update on the evidence for the efficacy and safety of rituximab in the management of neuromyelitis optica

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