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. 2023 Jun 1;18(6):759-766.
doi: 10.2215/CJN.0000000000000145. Epub 2023 Apr 10.

Proteinuria and Exposure to Eculizumab in Atypical Hemolytic Uremic Syndrome

Mendy Ter Avest  1 , Hilbert Steenbreker  1 , Romy N Bouwmeester  2 , Caroline Duineveld  3 , Kioa L Wijnsma  2 , Lambertus P W J van den Heuvel  2   4 , Saskia M C Langemeijer  5 , Jack F M Wetzels  3 , Nicole C A J van de Kar  2 , Rob Ter Heine  1 ; CUREiHUS Study Group
Affiliations

Proteinuria and Exposure to Eculizumab in Atypical Hemolytic Uremic Syndrome

Mendy Ter Avest et al. Clin J Am Soc Nephrol. .

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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Figures

None
Graphical abstract
Figure 1
Figure 1
Urinary protein-creatinine ratios (UPCR) for each patient over time. The black dotted line represents a protein-creatinine ratio of 3.3 g/g (severe proteinuria).
Figure 2
Figure 2
Percentage of patients with inadequate complement inhibition (classical pathway [CP] activity >10%) in the initial phase. (A) Percentage of adult patients with inadequate complement inhibition (classical pathway activity >10%) after an eculizumab dose during the initial phase for each degree of proteinuria. (B) Results for pediatric patients.
Figure 3
Figure 3
Percentage of patients with inadequate complement inhibition (classical pathway [CP] activity >10%) after an eculizumab dose during the maintenance phase for each degree of proteinuria. (A) Two-weekly interval in adult patients. (B) Three-weekly interval in adult patients. (C) Two-weekly interval in pediatric patients. (D) Three-weekly interval in pediatric patients.
Figure 4
Figure 4
Box plots for eculizumab trough concentration for each degree of proteinuria. The dotted line represents an eculizumab concentration of 50 mg/L (threshold for efficacy). (A) First loading dose in adult patients. (B) First loading dose in pediatric patients. (C) Two-weekly interval during maintenance phase in adult patients. (D) Two-weekly interval during maintenance phase in pediatric patients. (E) Three-weekly interval during maintenance phase in adult patients. (F) Three-weekly interval during maintenance phase in pediatric patients.
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References

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