Pharmacokinetic Characterization of Rituximab in Patients with Glomerular Diseases.

Abstract

Background: Rituximab is commonly used to treat patients with primary glomerular diseases; however, its pharmacokinetics in this population have not been fully described yet.

Materials and methods: This single-center, open-label, uncontrolled clinical trial included adult patients with glomerular diseases who required rituximab treatment (NEFRTX; EudraCT: 2020-000484-23). Patients received 1 or 0.5 g of rituximab on day 1 (and d14 in some cases). Blood and urine samples were collected at days 1, 7, 14, 28, and 45 to measure biochemical parameters (proteinuria, albuminemia, plasma immunoglobulin, and urine immunoglobulin), rituximab, and antidrug antibody concentrations. The gene encoding the neonatal fragment-crystallizable receptor was also characterized. Linear regression and Win-Nonlin 1.1 were used for pharmacokinetic analysis.

Results: Thirty-five cases (30 patients) were included in this study. Pharmacokinetic parameters were expressed as mean (SD): maximum plasma concentration, 179.4 (71.8) mcg/mL; volume of distribution, 78.9 (31.4) mL/kg; clearance, 0.30 (0.27) mL/h/kg; half-life (t1/2), 11.6 (5.8) d; elimination rate constant, 0.0036 (0.0030) hour-1; and area under the curve, 117,756.1 (88,228.1) mcg·h/mL. Antidrug antibody was detected on d1 in 3 cases (8.6%) and was negative by d28.Rituximab t1/2 was represented by the formula: t1/2 = A-B·Log (Proteinuria)+C·Albuminemia, where A = 515.1 (128.8-901.3), B = 182.1 (-108.6 to -35.4), and C = 39.5 (-10.9 to 89.9).There were significant differences in rituximab t1/2 based on diagnosis (P = 0.025), early treatment (P = 0.008), proteinuria >2.4g/24h (P < 0.001), plasma immunoglobulin <650 mg/dL (P = 0.048), and detectable urine immunoglobulin (P = 0.018).

Conclusions: Albuminemia and proteinuria affect rituximab t1/2 and drug exposure in patients with glomerular diseases. Patients with proteinuria >2.4g/24h may require higher frequent dosing for adequate rituximab exposure. Establishing an optimal dosing regimen in this population remains warranted.