Mendy Ter Avest, Saskia M C Langemeijer, Lambertus P W J van den Heuvel, Laura M Baas, Nicole C A J van de Kar, Rob Ter Heine
{"title":"Eculizumab在阵发性夜间血红蛋白尿患者中的精确给药","authors":"Mendy Ter Avest, Saskia M C Langemeijer, Lambertus P W J van den Heuvel, Laura M Baas, Nicole C A J van de Kar, Rob Ter Heine","doi":"10.1007/s40262-025-01536-x","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Clinical trial registration: </strong>ClincialTrials.gov identifier: NCT04079257.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":"1139-1147"},"PeriodicalIF":4.6000,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263743/pdf/","citationCount":"0","resultStr":"{\"title\":\"Model-Informed Precision Dosing of Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria.\",\"authors\":\"Mendy Ter Avest, Saskia M C Langemeijer, Lambertus P W J van den Heuvel, Laura M Baas, Nicole C A J van de Kar, Rob Ter Heine\",\"doi\":\"10.1007/s40262-025-01536-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Clinical trial registration: </strong>ClincialTrials.gov identifier: NCT04079257.</p>\",\"PeriodicalId\":10405,\"journal\":{\"name\":\"Clinical Pharmacokinetics\",\"volume\":\" \",\"pages\":\"1139-1147\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2025-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263743/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Pharmacokinetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s40262-025-01536-x\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/6/25 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Pharmacokinetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s40262-025-01536-x","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/25 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Model-Informed Precision Dosing of Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria.
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.
期刊介绍：
Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics.
Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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