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Review
. 2025 Aug;64(8):1139-1147.
doi: 10.1007/s40262-025-01536-x. Epub 2025 Jun 25.

Model-Informed Precision Dosing of Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria

Mendy Ter Avest  1 , Saskia M C Langemeijer  2 , Lambertus P W J van den Heuvel  3   4   5   6 , Laura M Baas  3 , Nicole C A J van de Kar  3 , Rob Ter Heine  7
Affiliations
Review

Model-Informed Precision Dosing of Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria

Mendy Ter Avest et al. Clin Pharmacokinet. 2025 Aug.

Abstract

Background and objective: Eculizumab is an expensive therapeutic monoclonal antibody inhibiting complement C5 and approved for various indications, including the rare disease paroxysmal nocturnal hemoglobinuria. Eculizumab is administered in a "one-dose-fits-all" dosing paradigm in adults, which is inflexible and suboptimal in some patients. Therefore, the aim of this study was to develop alternative dosing regimens that may improve patient friendliness or improve cost effectiveness.

Methods: A prospective observational pharmacokinetic study was conducted in 27 patients with paroxysmal nocturnal hemoglobinuria. The dataset was enriched with pharmacokinetic and pharmacodynamic data of a previous study of patients with atypical hemolytic uremic syndrome. A population pharmacokinetic/pharmacodynamic model was developed and this model was used to explore alternative and individualized dosing regimens.

Results: A two-compartment model with parallel linear and non-linear elimination best described the data. No intra-individual variability in clearance could be observed for patients with paroxysmal nocturnal hemoglobinuria in contrast to patients with atypical hemolytic uremic syndrome. An inhibitory Emax model described the relationship between plasma concentrations and complement activity. We predicted that only 52.0% of patients with paroxysmal nocturnal hemoglobinuria have adequate complement inhibition on day 7 with the standard loading dose, compared with 99.9% of the patients with an alternative weight-based loading dose, without an increase in treatment costs. A 4-weekly dosing regimen was developed and therapeutic drug monitoring will enable interval prolongation to 4 weeks without relevant increases in cumulative drug use compared to the approved dose.

Conclusions: The pharmacokinetics of eculizumab are similar in patients with atypical hemolytic uremic syndrome and patients with paroxysmal nocturnal hemoglobinuria, yet less variable in patients with paroxysmal nocturnal hemoglobinuria. Alternative dosing regimens can improve treatment in terms of efficacy and patient friendliness.

Clinical trial registration: ClincialTrials.gov identifier: NCT04079257.

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Conflict of interest statement

Declarations. Funding: No funding was received for the preparation of this article. Conflicts of Interest/Competing Interests: Nicole C.A.J. van de Kar and BvdH are members of the European Reference Network for Rare Kidney Diseases (ERKNet)-Project No 739532. Nicole C.A.J. van de Kar received consultancy fees from Roche Pharmaceuticals, Alexion, and Novartis and is a sub-investigator in the APL2-C3G trial, Apellis. Rob ter Heine has received research funding from Amgen. Mendy ter Avest, Saskia M.C. Langemeijer, Lambertus P.W.J van den Heuvel, and Laura M. Baas have no conflicts of interest that are directly relevant to the content of this article. Ethics Approval: Ethics approval number: NL69637.091.19, 22 July, 2019. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Availability of Data and Material: The participants of this study did not give written consent for their data to be shared publicly Code Availability: See Electronic Supplementary Material. Authors’ Contributions: MtA, SL, and RtH designed the research. MtA performed the research. LB analyzed the samples. MtA wrote the paper. Each author contributed important intellectual content during manuscript drafting or revision and all authors approved the final version.

Figures

Fig. 1
Fig. 1
Percentage of patients with classical pathway activity <10% (adequate therapy) in the initial phase and the maintenance phase. The red line represents patients who received standard dosing and the black line represents patients who received the alternative dosing strategy. A Initial phase, B therapeutic drug monitoring (TDM)-based maintenance phase, C weight-based 4-week interval, and D TDM-based 4-week interval. CP classical pathway activity
See this image and copyright information in PMC

References

    1. Hill A, DeZern AE, Kinoshita T, Brodsky RA. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers. 2017;18(3):17028. - PMC - PubMed
    1. Kelly R, Richards S, Hillmen P, Hill A. The pathophysiology of paroxysmal nocturnal hemoglobinuria and treatment with eculizumab. Ther Clin Risk Manage. 2009;5:911–21. - PMC - PubMed
    1. Takeda J, Miyata T, Kawagoe K, Iida Y, Endo Y, Fujita T, et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell. 1993;73(4):703–11. - PubMed
    1. Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18):2804–11. - PMC - PubMed
    1. Eculizumab. Summary of product characteristics. European Medicines Agency; 2012. https://www.ema.europa.eu/en/documents/product-information/soliris-epar-.... Accessed 19 Apr 2024.

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