Dosing optimization of rituximab for primary membranous nephropathy by population pharmacokinetic and pharmacodynamic study

Abstract

Primary membranous nephropathy (PMN) is the most common cause for adult nephrotic syndrome. Rituximab has demonstrated promising clinical efficacy by random controlled trials and the off-label use is widely adopted in PMN. However, the standard dosage is borrowed from B cell lymphoma treatment with far more antigens and is oversaturated for PMN treatment, accompanied with additional safety risk and unnecessary medical cost. More than 15% serious adverse events were observed under standard dosage and low dose therapies were explored recently. Dose optimization by clinical trials is extremely time- and cost-consuming and can be significantly accelerated with the aid of model-informed drug development. Here, we aim to establish the first population pharmacokinetic and pharmacodynamic (PPK/PD) model for rituximab in PMN to guide its dosage optimization. Rituximab pharmacokinetic and pharmacodynamic data from 41 PMN patients in a retrospective study under a newly proposed monthly mini-dose were used to construct quantitative dose-exposure-response relationship via mechanistic target-mediated drug disposition (TMDD) model followed by regression between the reduction of anti-PLA2R titer and time after the treatment. The final model, validated by goodness-of-fit plots, visual predictive checks and bootstrap, was used to recommend the optimized dosing regimen by simulations. The model was well validated for PK/PD prediction. The systemic clearance and half-life are 0.54 L/h and 14.7 days, respectively. Simulation of a novel regimen (6 monthly doses of 100 mg) indicated the comparable ability and superior duration time of CD20⁺ B cell depletion compared with standard dosage, while the cumulative dosage and safety risk was significantly decreased. We established the first PPK/PD model and provide evidence to support the dosage optimization based on monthly mini-dose. Our study can also efficiently accelerate dosage optimization of novel anti-CD20 antibodies in PMN and other indications.

Keywords: dosage optimization; population pharmacokinetic and pharmacodynamic; primary membranous nephropathy; rituximab; target-mediated drug disposition.

FIGURE 1

Goodness-of-fit plots for RTX of the final model. The red line is generated by linear method and shows the trend of the data, and the blue circles represent the observed data.

FIGURE 2

Goodness-of-fit plots for CD20 of the final model. The red line is generated by linear method and shows the trend of the data, and the blue circles represent the observed data.

FIGURE 3

Simulation of RTX concentration after infusion of (A) four weekly 375 mg/m² RTX; (B) two 1000 mg RTX with two weeks apart; (C) six monthly 100 mg RTX; (D) three 100 mg RTX with two months apart. The solid line represents the mean RTX concentration versus time, while the shadow represents the 90% prediction intervals.

FIGURE 4

Simulation of CD20⁺ B cell counts after infusion of (A) four weekly 375 mg/m² RTX; (B) two 1000 mg RTX with two weeks apart; (C) six monthly 100 mg RTX; (D) three 100 mg RTX with two months apart. The solid line represents the mean CD20⁺ B cell counts versus time, while the shadow represents the 90% prediction intervals. Dashed line indicated CD20⁺ B cell depletion criterion (5/μL).