Pharmacokinetic characterization of rituximab in patients with
glomerular diseases
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.