Proteinuria and Exposure to Eculizumab in Atypical Hemolytic Uremic Syndrome.

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. As proteinuria may impact the pharmacokinetics of therapeutic proteins like 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 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 two-weekly and three-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 >3.5g/10mmol or >3.1 g/g) will have inadequate complement inhibition (classical pathway activity >10%) on day 7 of treatment, compared to 3% of the adult patients without proteinuria. None of the pediatric patients will have inadequate complement inhibition at day 7 of treatment. For the two- and three-weekly dosing interval, 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 to 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.