The Influence of Underlying Disease on Rituximab Pharmacokinetics May be Explained by Target-Mediated Drug Disposition

Bensalem, Amina; Cartron, Guillaume; Specks, Ulrich; Mulleman, Denis; Gyan, Emmanuel; Cornec, Divi; Desvignes, Céline; Casasnovas, Olivier; Lamy, Thierry; Leprêtre, Stéphane; Paintaud, Gilles; Ternant, David

doi:10.1007/s40262-021-01081-3

Cited by 9 publications

(9 citation statements)

References 39 publications

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“…Several studies have reported a mild to large interindividual variability of RTX PK in AAV patients. Consistent with those studies (8,12,13,22,23), we observed a large interindividual variability in RTX plasma CM3. In univariate analysis, the main determinants of RTX PK were gender, BMI, CRP >10 mg/liter, and ANCA status at inclusion as previously reported for gender and BMI (22), but the multivariate analysis failed to identify any independent factor.…”

Section: Discussionsupporting

confidence: 92%

Association Between Plasma Rituximab Concentration and the Risk of Major Relapse in Antineutrophil Cytoplasmic Antibody–Associated Vasculitides During Rituximab Maintenance Therapy

Khoudour

Delestre

Jabot–Hanin

et al. 2023

Arthritis & Rheumatology

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ObjectiveInterindividual variability in response to rituximab remains unexplored in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides. Rituximab pharmacokinetics (PK) and pharmacodynamics (PD) as well as genetic polymorphisms could contribute to variability. This ancillary study of the MAINRITSAN 2 trial aimed to explore the relationship between rituximab plasma concentration, genetic polymorphisms in PK/PD candidate genes, and clinical outcomes.MethodsPatients included in the MAINRITSAN2 trial (ClinicalTrials.gov identifier: NCT01731561) were randomized to receive a 500‐mg fixed‐schedule rituximab infusion or an individually tailored regimen. Rituximab plasma concentrations at month 3 (CM3) were assessed. DNA samples (n = 53) were genotyped for single‐nucleotide polymorphisms within 88 putative PK/PD candidate genes. The relationship between PK/PD outcomes and genetic variants was investigated using logistic linear regression in additive and recessive genetic models.ResultsOne hundred and thirty‐five patients were included. The frequency of underexposed patients (<4 μg/ml) in the fixed‐schedule group was statistically lower compared to that in the tailored‐infusion group (2.0% versus 18.0%; P = 0.02, respectively). Low rituximab plasma concentration at 3 months (CM3 <4 μg/ml) was an independent risk factor for major relapse (odds ratio 6.56 [95% confidence interval (95% CI) 1.26–34.09]; P = 0.025) at month 28 (M28). A sensitivity survival analysis also identified CM3 <4 μg/ml as an independent risk factor for major relapse (hazard ratio [HR] 4.81 [95% CI 1.56–14.82]; P = 0.006) and relapse (HR 2.70 [95% CI 1.02–7.15]; P = 0.046). STAT4 rs2278940 and PRKCA rs8076312 were significantly associated with CM3 but not with major relapse onset at M28.ConclusionThese results suggest that drug monitoring could be useful to individualize the schedule of rituximab administration within the maintenance phase.

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Section: Discussionsupporting

confidence: 92%

Association Between Plasma Rituximab Concentration and the Risk of Major Relapse in Antineutrophil Cytoplasmic Antibody–Associated Vasculitides During Rituximab Maintenance Therapy

Khoudour

Delestre

Jabot–Hanin

et al. 2023

Arthritis & Rheumatology

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“…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 ).…”

Section: The Pharmacokinetics Of Rituximab and The Covariates That In...mentioning

confidence: 99%

“…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 ).…”

Section: The Pharmacokinetics Of Rituximab and The Covariates That In...mentioning

confidence: 99%

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

Hartinger

Krátký²,

Hrušková³

et al. 2022

Front. Immunol.

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The specific B-cell depleting anti-CD20 monoclonal antibody rituximab (RTX) is effective in terms of the treatment of various immune-mediated glomerulopathies. The administration of RTX has been shown to be reliable and highly effective particularly in patients with ANCA-associated vasculitis, which is manifested predominantly with non-nephrotic proteinuria. Stable long-term B-cell depletion is usually readily attained in such patients using standard dosing regimens. However, in patients with nephrotic syndrome and non-selective proteinuria, the RTX pharmacokinetics is altered profoundly and RTX does not maintain high enough levels for a sufficiently long period, which may render RTX treatment ineffective. Since complement-derived cytotoxicity is one of the important modes of action of RTX, hypocomplementemia, frequently associated with systemic lupus erythematodes, may act to hamper the efficacy of RTX in the treatment of patients with lupus nephritis. This review provides a description of RTX pharmacokinetics and pharmacodynamics in several selected glomerulopathies, as well as the impact of proteinuria, anti-drug antibodies and other clinical variables on the clearance and volume of distribution of RTX. The impact of plasmapheresis and peritoneal dialysis on the clearance of RTX is also discussed in the paper. A review is provided of the potential association between pharmacokinetic and pharmacodynamic alterations in various kidney-affecting glomerular diseases, the sustainability of B-cell depletion and the clinical efficacy of RTX, with proposals for potential dosing implications. The role of therapeutic drug monitoring in treatment tailoring is also discussed, and various previously tested RTX dosing schedules are compared in terms of their clinical and laboratory treatment responses. Since alternative anti-CD20 molecules may prove effective in RTX unresponsive patients, their pharmacokinetics, pharmacodynamics and current role in the treatment of glomerulopathies are also mentioned.

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“…The dosage was borrowed from B cell lymphoma treatment and recommended as four weekly infusions of 375 mg/m 2 or two 1000 mg infusions with 2 weeks apart ( Rovin et al, 2021 ). However, the B cell counts in PMN patients are only 1/300 of that in lymphoma patients., Thus, the standard dose may be oversaturated for B cell depletion in PMN patients even with the urinary loss of rituximab and cause unnecessary medical cost ( Bensalem et al, 2022 ), though the safety risk is relatively low when compared with other immunosuppressive drugs ( Fervenza et al, 2019 ). It is still debatable for the relationship between larger doses and improved clinical outcomes.…”

Section: Introductionmentioning

confidence: 99%

“…Model-informed drug development strategy is a powerful tool to aid and accelerate dose optimization by constructing the quantitative dose-exposure-response relationship and accurately predicting the clinical efficacy of different regimens in advance ( Cardone et al, 2011 ). However, the pharmacokinetic (PK) characteristics were rarely described for RTX in PMN treatment and the pharmacokinetic and pharmacodynamic (PK/PD) relationship of RTX has not been established yet ( Bensalem et al, 2022 ). Although CD20 + B cell depletion is not the clinical endpoint for the treatment of PMN, it can serve as an efficient surrogate that bridge the PK of RTX and clinical efficacy.…”

Section: Introductionmentioning

confidence: 99%

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

Liang,

Deng,

Niu

et al. 2024

Front. Pharmacol.

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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.

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The Influence of Underlying Disease on Rituximab Pharmacokinetics May be Explained by Target-Mediated Drug Disposition

Cited by 9 publications

References 39 publications

Association Between Plasma Rituximab Concentration and the Risk of Major Relapse in Antineutrophil Cytoplasmic Antibody–Associated Vasculitides During Rituximab Maintenance Therapy

Association Between Plasma Rituximab Concentration and the Risk of Major Relapse in Antineutrophil Cytoplasmic Antibody–Associated Vasculitides During Rituximab Maintenance Therapy

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

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

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