AI Article Synopsis
- - The study focuses on how proteinuria (high levels of protein in urine) affects the pharmacokinetics of eculizumab, a treatment for atypical hemolytic uremic syndrome (aHUS), as kidney damage can lead to proteinuria.
- - Researchers analyzed urine protein-creatinine ratios to see how they influenced the clearance of eculizumab, finding that higher proteinuria levels resulted in a statistically significant reduction in eculizumab effectiveness for some patients.
- - Results indicated that adults with severe proteinuria were more likely to have inadequate response to eculizumab treatment compared to those without proteinuria, highlighting the need for careful monitoring and potential dose adjustments in these patients.
Article Abstract
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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278783 | PMC |
| http://dx.doi.org/10.2215/CJN.0000000000000145 | DOI Listing |
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