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Pharmacokinetic characterization of rituximab in patients with glomerular diseases
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  • Maria Larrosa-Garcia,
  • Roxana-Paola Bury Macías,
  • María Sanz Martínez,
  • Mónica Martínez Gallo,
  • Roger Colobran,
  • Sonia García-García ,
  • Manuel Hernández González,
  • Irene Agraz Pamplona,
  • Bruno Montoro-Ronsano
Maria Larrosa-Garcia
Vall d'Hebron University Hospital

Corresponding Author:maria.larrosa@vallhebron.cat

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Roxana-Paola Bury Macías
Vall d'Hebron University Hospital
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María Sanz Martínez
Vall d'Hebron University Hospital
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Mónica Martínez Gallo
Vall d'Hebron University Hospital
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Roger Colobran
Vall d'Hebron University Hospital
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Sonia García-García
Vall d'Hebron University Hospital
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Manuel Hernández González
Vall d'Hebron University Hospital
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Irene Agraz Pamplona
Vall d'Hebron University Hospital
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Bruno Montoro-Ronsano
Hospital Universitari Vall d'Hebron
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Abstract

Rituximab is used for several indications including primary glomerulopathies; however, the optimal schedule in those diseases remains to be established. The aim of this study is to characterize rituximab pharmacokinetics in a population affected with glomerular diseases. A single-center, open-labelled, uncontrolled clinical trial was performed including adults affected by glomerular diseases who required rituximab (NEFRTX, EudraCT: 2020-000484-23). Patients received 1g or 0.5g of rituximab on day 1 (and 14 in some cases); blood and urine samples were collected. Rituximab and anti-rituximab concentrations were measured and the gene encoding the neonatal fragment crystallizable receptor (FcRn) was characterized. Win-Nonlin 1.1, was used for pharamacokinetic analysis. Thirty-five cases (30 patients) were included. Pharmacokinetic parameters (mean ± standard deviation): maximum plasma concentration 179.4±71.8µg/ml, volume of distribution 78.9±31.4ml/kg, clearance 0.30±0.27ml/h/kg, half-life (t1/2) 11.6±5.8d, elimination rate constant 0.0036±0.0030h⁻¹, area under the curve 117,756.1±88,228.1µg·h/ml. Anti-rituximab was detected on d1 in 3(8.6%) cases, they were negative by d28. No infusion reactions occurred. Rituximab t1/2 was characterized by the formula: t1/2=A-B·Log (Proteinuria)+C·Albuminemia; where A=515.0 (128.8, 901.3), B=182.1 (-108.6, -35.4), C=39.5 (-10.9, 89.9). There were differences in rituximab t1/2 depending on the presence of 24-hours proteinuria>2.4 g/24h (p<0.001), early treatment (p=0.008), diagnosis (p=0.025) and IgG<650 mg/dL (p=0.048). Our study confirms that albuminemia and especially proteinuria affect rituximab t1/2 and drug exposure in patients with primary glomerulopathies. Patients affected by membranous nephropathy and/or nephrotic syndrome and/or proteinuria >2.4 g/24h and/or IgG <650 mg/dl could need more frequent dosing. Further research is needed to establish an optimal dosing strategy in this population.