دورية أكاديمية
أعرض في EDS

Proposal for individualized dosing of eculizumab in atypical haemolytic uraemic syndrome: patient friendly and cost-effective.

التفاصيل البيبلوغرافية
العنوان: Proposal for individualized dosing of eculizumab in atypical haemolytic uraemic syndrome: patient friendly and cost-effective.
المؤلفون: Ter Avest M; Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands., Bouwmeester RN; Department of Paediatric Nephrology, Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, Radboud University Medical Centre, Nijmegen, The Netherlands., Duineveld C; Department of Nephrology, Radboud University Medical Centre, Nijmegen, The Netherlands., Wijnsma KL; Department of Paediatric Nephrology, Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, Radboud University Medical Centre, Nijmegen, The Netherlands., Volokhina EB; Department of Paediatric Nephrology, Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, Radboud University Medical Centre, Nijmegen, The Netherlands.; Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands., van den Heuvel LPWJ; Department of Paediatric Nephrology, Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, Radboud University Medical Centre, Nijmegen, The Netherlands.; Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands., Burger DM; Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands., Wetzels JFM; Department of Nephrology, Radboud University Medical Centre, Nijmegen, The Netherlands., van de Kar NCAJ; Department of Paediatric Nephrology, Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, Radboud University Medical Centre, Nijmegen, The Netherlands., Ter Heine R; Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
مؤلفون مشاركون: CUREiHUS study group
المصدر: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association [Nephrol Dial Transplant] 2023 Feb 13; Vol. 38 (2), pp. 362-371.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 8706402 Publication Model: Print Cited Medium: Internet ISSN: 1460-2385 (Electronic) Linking ISSN: 09310509 NLM ISO Abbreviation: Nephrol Dial Transplant Subsets: MEDLINE
أسماء مطبوعة: Publication: Oxford : Oxford University Press
Original Publication: [Berlin ; New York, NY] : Springer International, [c1986-
مواضيع طبية MeSH: Atypical Hemolytic Uremic Syndrome*/drug therapy, Humans ; Cost-Benefit Analysis ; Antibodies, Monoclonal, Humanized/therapeutic use
مستخلص: Background: Eculizumab is a lifesaving yet expensive drug for atypical haemolytic uraemic syndrome (aHUS). Current guidelines advise a fixed-dosing schedule, which can be suboptimal and inflexible in the individual patient.
Methods: We evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) [classical pathway (CP) activity levels] of eculizumab in 48 patients, consisting of 849 time-concentration data and 569 CP activity levels. PK-PD modelling was performed with non-linear mixed-effects modelling. The final model was used to develop improved dosing strategies.
Results: A PK model with parallel linear and non-linear elimination rates best described the data with the parameter estimates clearance 0.163 L/day, volume of distribution 6.42 L, maximal rate 29.6 mg/day and concentration for 50% of maximum rate 37.9 mg/L. The PK-PD relation between eculizumab concentration and CP activity was described using an inhibitory Emax model with the parameter estimates baseline 101%, maximal inhibitory effect 95.9%, concentration for 50% inhibition 22.0 mg/L and  Hill coefficient 5.42. A weight-based loading dose, followed by PK-guided dosing was found to improve treatment. On day 7, we predict 99.95% of the patients to reach the efficacy target (CP activity <10%), compared with 94.75% with standard dosing. Comparable efficacy was predicted during the maintenance phase, while the dosing interval could be prolonged in ∼33% of the population by means of individualized dosing. With a fixed-dose 4-week dosing interval to allow for holidays, treatment costs will increase by 7.1% and we predict 91% of the patients will reach the efficacy target.
Conclusions: A patient-friendly individualized dosing strategy of eculizumab has the potential to improve treatment response at reduced costs.
(© The Author(s) 2022. Published by Oxford University Press on behalf of ERA.)
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فهرسة مساهمة: Investigator: E van Kempen; W Altena; E Adang; DJAR Moes; AD van Zuijlen; SP Berger; FJ Bemelman; JW van der Heijden; J van de Wetering; APJ de Vries; P van Paasen; JFM Wetzels; JAE van Wijk; AHM Bouts; EM Dorresteijn; V Gracchi; FAPTH Engels; MG Keijzer-Veen; RWG van Rooij; NCAJ van de Kar
Keywords: aHUS; complement; eculizumab; pharmacodynamics; pharmacokinetics
المشرفين على المادة: A3ULP0F556 (eculizumab)
0 (Antibodies, Monoclonal, Humanized)
تواريخ الأحداث: Date Created: 20220303 Date Completed: 20230214 Latest Revision: 20230918
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC9923710
DOI: 10.1093/ndt/gfac056
PMID: 35238929
قاعدة البيانات: MEDLINE
الوصف
تدمد:1460-2385
DOI:10.1093/ndt/gfac056