Proteinuria and Exposure to Eculizumab in Atypical Hemolytic Uremic Syndrome
| Autor: | Avest, M. ter, Steenbreker, H., Bouwmeester, R.N., Duineveld, C., Wijnsma, K.L., Heuvel, L.P.W.J. van den, Langemeijer, S.M.C., Wetzels, J.F.M., Kar, N.C.A.J. van de, Heine, R. ter |
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| Rok vydání: | 2023 |
| Předmět: |
Cancer development and immune defence Radboud Institute for Health Sciences [Radboudumc 2]
All institutes and research themes of the Radboud University Medical Center Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] |
| Zdroj: | Clinical Journal of the American Society of Nephrology, 18, 6, pp. 759-766 Clinical Journal of the American Society of Nephrology, 18, 759-766 |
| ISSN: | 1555-9041 |
| Popis: | Item does not contain fulltext BACKGROUND: Eculizumab is a monoclonal antibody for the treatment of atypical hemolytic uremic syndrome (aHUS). Kidney damage, a common condition in patients with aHUS, may result in proteinuria. Because proteinuria may affect the pharmacokinetics of therapeutic proteins such as eculizumab, the aim of our study was to investigate the effect of proteinuria on eculizumab pharmacokinetics. METHODS: This study was an ancillary study of a previously performed pharmacokinetic-pharmacodynamic study of eculizumab in aHUS. Proteinuria, measured as urinary protein-creatinine ratios (UPCR), was investigated as covariate for eculizumab clearance. Thereafter, we evaluated the effect of proteinuria on the exposure to eculizumab in a simulation study for the initial phase and for a 2-weekly and 3-weekly interval in the maintenance phase. RESULTS: The addition of UPCR as a linear covariate on clearance to our base model resulted in a statistically improved fit ( P < 0.001) and reduction of unexplained variability in clearance. From our data, we predicted that in the initial phase, 16% of the adult patients with severe proteinuria (UPCR >3.1 g/g) will have inadequate complement inhibition (classical pathway activity >10%) on day 7 of treatment, compared with 3% of the adult patients without proteinuria. None of the pediatric patients will have inadequate complement inhibition at day 7 of treatment. For the 2- and 3-weekly dosing intervals, we predicted that, respectively, 18% and 49% of the adult patients and, respectively, 19% and 57% of the pediatric patients with persistent severe proteinuria will have inadequate complement inhibition, compared with, respectively, 2% and 13% of the adult patients and, respectively, 4% and 22% of the pediatric patients without proteinuria. CONCLUSIONS: Severe proteinuria is associated with a higher risk of underexposure to eculizumab. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: CUREiHUS, Dutch Trial Register, NTR5988/NL5833. |
| Databáze: | OpenAIRE |
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