The Influence of Different Disease States on Rituximab Pharmacokinetics

Abstract

Background: The anti-CD20 antibody rituximab, which promotes the selective depletion of CD20 positive B cells, was the first targeted therapy that was approved for the treatment of B-cell malignancies, and it is now widely prescribed in both malignant and non-malignant, immune-related diseases. However, the cause of its various clinical responses in certain diseases, have not been clearly elucidated. The variabilities in inter-individual pharmacokinetic and the emerging evidence of the relationships between pharmacokinetic and pharmacodynamic may provide a better understanding of this drug. Methods: We searched and summarized the latest published articles on rituximab pharmacokinetic profiles and the pharmacokinetic/pharmacodynamic models in different patient populations, including B-cell malignancies, rheumatoid arthritis, ANCA-associated vasculitis, and glomerular kidney diseases. Results: Most pharmacokinetic data are drawn from clinical studies in oncology clinical practice. Body weight, gender, and antigen-related factors are proven to be the key factors affecting rituximab pharmacokinetics. In addition, the positive exposure-response relations were reported, which provides encouraging evidence for individualized therapies. While in immune disorders, especially in the off-labeled indications, pharmacokinetic studies are quite limited. Compared with that in B-cell malignancies, the differences in the pharmacokinetic parameters may be attributed to the different pathogeneses of diseases, mechanisms of action and dosing strategies. However, the correlation between drug exposure and clinical outcomes remains unclear. Conclusion: Here we provide an overview of the complexities associated with rituximab pharmacokinetics and pharmacodynamics in different diseases. Although many influencing factors need to be verified in future studies, a better understanding of the relationships between pharmacokinetic and pharmacodynamic may assist in optimizing rituximab clinical practice.

Humoral and cellular responses to mRNA vaccines against SARS-CoV-2 in patients with a history of CD20 B-cell-depleting therapy (RituxiVac): an investigator-initiated, single-centre, open-label study

“… 9 The high variability of pharmacokinetics and thereby B-cell recovery times makes it difficult to define ideal vaccination timepoints and to predict immune responses to vaccines. 10 There is an urgent need for evidence-based recommendations for administration of SARS-CoV-2 vaccines in immunocompromised patients, since in the absence of randomised controlled trials, current recommendations to delay B-cell-depleting therapies are based on previous influenza vaccination studies 7 and emerging humoral data on immune responses to SARS-CoV-2 vaccines in immunocompromised patients. 11 , 12 , 13 , 14 , 15 , 16 An improved understanding of humoral and cell-mediated responses following vaccination against SARS-CoV-2 in patients treated with anti-CD20-depleting agents is a prerequisite for the development of individualised vaccination strategies for this population.…”

Rituximab Concentration Varies in Patients With Different Lymphoma Subtypes and Correlates With Clinical Outcome

“…Almost all clinical studies in which rituximab serum levels have been evaluated have demonstrated that the observed large interindividual variability in rituximab serum levels could be related to the "target burden" (Cartron et al, 2007;Golay et al, 2013;Wang et al, 2020). It is not surprising that the baseline CD19 + lymphocyte count was found to be inversely correlated with the rituximab level, a higher concentration of rituximab would be needed to neutralize the high amount of circulating B cells in the peripheral blood.…”

Implications of rituximab pharmacokinetic and pharmacodynamic alterations in various immune-mediated glomerulopathies and potential anti-CD20 therapy alternatives

“…The pharmacokinetics of RTX in patients differs according to disease type and activity (57), with one of the most altered pharmacokinetic profiles having been described in MN patients during periods with high levels of non-selective proteinuria (11). Pharmacokinetic parameters described in different studies vary due both to the different diseases studied and the different pharmacokinetic models and analytical methods applied (10). Therefore, Bensalem et al used concentration-time data from 5 different studies and applied the same method to calculate RTX pharmacokinetic characteristics.…”

“…Than they compared pharmacokinetic characteristics of five different diseases and found out that there are profound differences between autoimmune and hematological diseases ( 57 ). Generally, RTX (as well as other MABs) pharmacokinetic is best described by means of a two compartmental model with a central plasmatic compartment and a peripheral tissue compartment with the occurrence of elimination in the central or both of these compartments ( 10 , 11 , 58 , 59 ). During the treatment of most autoimmune diseases RTX has relatively stable half-life whereas its half-life in hematologic diseases typically prolongs during the treatment as the excessive number of target cells decrease ( 60 ).…”

“…It has been proven that RTX pharmacokinetics is influenced by several clinical covariates, namely the severity of the disease, antigen derived factors (e.g. the amount of antigen in the tissues), gender, body weight and the selectivity of proteinuria (PU), which may act to alter the response to treatment ( 10 ). Moreover, the potential formation of anti-RTX antibodies may result in decreased treatment effectivity ( 11 , 12 ).…”