Monitoring Ravulizumab effect on complement assays

Willrich, Maria Alice V.; Ladwig, Paula M.; Martinez, Mark; Sridharan, Meera; Go, Ronald S.; Murray, David

doi:10.1016/j.jim.2020.112944

Cited by 13 publications

(12 citation statements)

References 8 publications

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“…For the liposomal assay for CP activity in four rounds of testing (2020 and 2021), the passing quota for the pathogenic sample was ≤80%. These results are consistent with other publications suggesting that this method of measuring CP function is ideal for measuring low level activity ( 42 , 43 ). However, it should be noted that in more recent rounds the passing quota for the pathological samples improved to greater than 90%.…”

Section: Discussionsupporting

confidence: 93%

External quality assurance program for diagnostic complement laboratories: evaluation of the results of the past seven years

Kirschfink,

Frazer-Abel,

Balogh

et al. 2024

Front. Immunol.

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IntroductionThe complement external quality assurance (EQA) program was first organized in 2010 by a group of researchers working in diagnostic complement laboratories. Starting in 2016, INSTAND e.V., a German, non-profit interdisciplinary scientific medical society dedicated to providing expert EQA programs for medical laboratories, started organizing the EQAs for complement diagnostic laboratories together with the same group of experienced scientists and doctors who also work as EQA experts. The aim of the current work is to provide descriptive analysis of the past seven years’ complement EQA results and evaluate timeline changes in proficiency testing.MethodsEach year, in March and October, blinded samples (normal, pathological) were sent to the participating diagnostic laboratories, where complement parameters were evaluated exactly as in daily routine samples. Since no reference method/target values exist for these parameters, and participants used different units for measurement, the reported results were compared to the stable mean (Algorithm A) of the participants using the same method/measurement units. A reported result was qualified as “passed” if it fell into the 30-50% evaluation/target range around the mean of reported results (depending on the given parameter).ResultsWhile the number of participating laboratories has increased in the past years (from around 120 to 347), the number of complement laboratories providing multiple determinations remained mostly unchanged (around 30 worldwide). C3, C4, C1-inhibitor antigen and activity determinations provided the best proficiency results, with >90% passing quotas in the past years, independent of the applied method. Determination of the functional activity of the three activation pathways was good in general, but results showed large variance, especially with the pathological samples. Complement factor C1q and regulators FH and FI are determined by only a few laboratories, with variable outcomes (in general in the 85-90% pass range). Activation products sC5b-9 and Bb were determined in 30 and 10 laboratories, respectively, with typical passing quotas in the 70-90% range, without a clear tendency over the past years.ConclusionWith these accumulated data from the past seven years, it is now possible to assess sample-, method-, and evaluation related aspects to further improve proficiency testing and protocolize diagnostic complement determinations.

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Section: Discussionsupporting

confidence: 93%

External quality assurance program for diagnostic complement laboratories: evaluation of the results of the past seven years

Kirschfink,

Frazer-Abel,

Balogh

et al. 2024

Front. Immunol.

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“…However, the same complement tests (i.e., CH50 and sC5b-9) used for eculizumab may not consistently indicate adequate complement blockade (free C5 < 0.5 μg/mL) in monitoring therapy with ravulizumab ( 20 ). While this is an active area of research ( 21 , 22 ), recent studies suggest that ravulizumab offers a cost-savings and improved quality of life with less frequent dosing compared to the current cost of eculizumab ( 23 ) and adapted monitoring parameters (such as free C5 assays) are expected to be useful in individualizing the dosing of this drug as well.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Atypical HUS Presenting With Acute Rhabdomyolysis Highlights the Need for Individualized Eculizumab Dosing

et al. 2022

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BackgroundAtypical hemolytic uremic syndrome (aHUS) is an ultra-rare orphan disease caused by dysregulated complement activation resulting in thrombotic microangiopathy. Although complement-mediated endothelial injury predominantly affects the renal microvasculature, extra-renal manifestations are present in a significant proportion of patients. While eculizumab has significantly improved the morbidity and mortality of this rare disease, optimizing therapeutic regimens of this highly expensive drug remains an active area of research in the treatment of aHUS.Case PresentationThis report describes the case of a previously healthy 4 year-old male who presented with rhabdomyolysis preceding the development of aHUS with anuric kidney injury requiring dialysis. Clinical stabilization required increased and more frequent eculizumab doses compared with the standardized weight-based guidelines. In the maintenance phase of his disease, pharmacokinetic analysis indicated adequate eculizumab levels could be maintained with an individualized dosing regimen every 3 weeks, as opposed to standard 2 week dosing, confirmed in this patient over a 4 year follow up period. Cost analyses show that weight-based maintenance dosing costs $312,000 per year, while extending the dosing interval to every 3 weeks would cost $208,000, a savings of $104,000 per year, relative to the cost of $72,000 from more frequent eculizumab dosing during his initial hospitalization to suppress his acute disease.ConclusionThis case exemplifies the potential of severe, multisystem involvement of aHUS presenting with extra-renal manifestations, including rhabdomyolysis as in this case, and highlights the possibility for improved clinical outcomes and higher value care with individualized eculizumab dosing in patients over the course of their disease.

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“…It is likely that RAVUL use will improve quality of life for patients even more, given its favorable dosing regimen every 8 weeks when contrasted to ECUL every 2 weeks. For aHUS patients achieving remission on RAVUL, TDM and discontinuation of therapy may become hot topics, and strategies to measure both complement blockage using assays such as AH50 [18] , and drug quantitation that can accurately measure the t-mAb will prove as helpful tools to clinicians enrolling patients in such studies in the near future.…”

Section: Discussionmentioning

confidence: 99%

Ravulizumab: Characterization and quantitation of a new C5 inhibitor using isotype specific affinity purification and high-resolution mass spectrometry

Ladwig

Willrich

2021

Journal of Mass Spectrometry and Advances in the Clinical Lab

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Monitoring Ravulizumab effect on complement assays

Cited by 13 publications

References 8 publications

External quality assurance program for diagnostic complement laboratories: evaluation of the results of the past seven years

External quality assurance program for diagnostic complement laboratories: evaluation of the results of the past seven years

Case Report: Atypical HUS Presenting With Acute Rhabdomyolysis Highlights the Need for Individualized Eculizumab Dosing

Ravulizumab: Characterization and quantitation of a new C5 inhibitor using isotype specific affinity purification and high-resolution mass spectrometry

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