Non-Linear Rituximab Pharmacokinetics and Complex Relationship between Rituximab Concentrations and Anti-Neutrophil Cytoplasmic Antibodies (ANCA) in ANCA-Associated Vasculitis: The RAVE Trial Revisited

Bensalem, Amina; Mulleman, Denis; Paintaud, Gilles; Azzopardi, Nicolas; Gouilleux-Gruart, Valérie; Cornec, Divi; Specks, Ulrich; Ternant, David

doi:10.1007/s40262-019-00826-5

Cited by 14 publications

(11 citation statements)

References 42 publications

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“…The depletion of B-cells in response to RTX treatment has been observed to be very stable in AAV patients, and the pharmacokinetics are very similar to those of other autoimmune diseases that do not affect the kidneys ( 74 ). Nevertheless, profound pharmacokinetic changes occur in other glomerulopathies that may act to hamper the efficacy of RTX treatment.…”

Section: Pharmacokinetic Alterations and The Response To Treatment Wi...mentioning

confidence: 93%

“…Low RTX levels allow for the prediction of hemato-oncologic disease relapses, which may suggest that the affected patients were underdosed for their particular tumor burden ( 58 ). RTX clearance is also enhanced in the case of a higher B-cell count in RA, and non-linear pharmacokinetics have also been proven in AAV, which is described in more detail in the text below ( 74 ).…”

Section: Factors That Influence the Clearance Of Rtxmentioning

confidence: 97%

“…The average half-life of RTX in AAV patients is 23 days, which corresponds to the average half-life of this drug in most other diseases ( 74 ). Cornec et al.…”

Section: The Variation In Rtx Pharmacokinetics In Various Glomerular ...mentioning

confidence: 99%

“…Generally, RTX led to a delayed decrease in ANCA antibodies, which were more sustained in MPO patients. The feedback exponent linked with the PR3 ANCA antibody was five times higher in patients with relapses, thus indicating that the levels of PR3-ANCA rebounded more rapidly in patients with relapsing disease ( 74 ).…”

Section: The Variation In Rtx Pharmacokinetics In Various Glomerular ...mentioning

confidence: 99%

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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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Section: Pharmacokinetic Alterations and The Response To Treatment Wi...mentioning

confidence: 93%

Section: Factors That Influence the Clearance Of Rtxmentioning

confidence: 97%

“…The average half-life of RTX in AAV patients is 23 days, which corresponds to the average half-life of this drug in most other diseases ( 74 ). Cornec et al.…”

Section: The Variation In Rtx Pharmacokinetics In Various Glomerular ...mentioning

confidence: 99%

Section: The Variation In Rtx Pharmacokinetics In Various Glomerular ...mentioning

confidence: 99%

See 2 more Smart Citations

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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show abstract

“…RTX levels correlate with ANCA titre decreases 118 but a reliable biomarker or cell population useful for monitoring disease activity, determining the time intervals of redosing and predicting relapses has not been found yet. Concerning this matter, study results are rather weak, not always comparable, or reproducible, often confusing and, though the raised expectations, rather disappointing.…”

Section: Histological Markers In Anca‐associated Vasculitismentioning

confidence: 99%

Monitoring disease activity in antineutrophil antibody‐associated vasculitis

Scurt

Hirschfeld²,

Schubert

et al. 2023

Scand J Immunol

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Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) comprises a group of multisystem disorders with alternating periods of relapse and remission. Beyond that, a smouldering progress during apparently clinically silent phases often develops. AAVs are subgrouped in microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA) and renal limited vasculitis (RLV). ANCA are hallmark of this disease entity, although they are not always present. Despite the simplification of treatment, fundamental aspects concerning assessment of its efficacy and its adaptation to encountered complications or to the relapsing/remitting/subclinical disease course remain still unknown. Through the advances in pathogenesis and pathophysiology of AAV a reliable biomarker-based monitoring and treatment algorithm has not been established and disease management follows not infrequently a "trial and error" approach. Here, we overviewed the most interesting biomarkers reported so far.

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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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Non-Linear Rituximab Pharmacokinetics and Complex Relationship between Rituximab Concentrations and Anti-Neutrophil Cytoplasmic Antibodies (ANCA) in ANCA-Associated Vasculitis: The RAVE Trial Revisited

Cited by 14 publications

References 42 publications

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

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

Monitoring disease activity in antineutrophil antibody‐associated vasculitis

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

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