Eculizumab Dosing Regimen in Atypical HUS: Possibilities for Individualized Treatment

Abstract

Recent studies indicate that eculizumab is often given in excess to atypical hemolytic uremic syndrome (aHUS) patients. Individualization of treatment is thus highly requested; however, data on the pharmacokinetics and pharmacodynamics of eculizumab remain limited. We analyzed 11 patients during induction (weekly), maintenance (2-weekly), and tapering (every 3-8 weeks) phases of treatment. The trough eculizumab levels increased with each additional dose during the induction phase (depending on body weight). During maintenance, high eculizumab concentrations of up to 772 μg/mL were observed. The levels decreased with each following dose during tapering (3- and 4-week intervals); however, three patients maintained target eculizumab levels over long time periods (30-48 weeks). At intervals of 6-8 weeks, target eculizumab levels were no longer attained. Serum samples with eculizumab concentrations ≥50 μg/mL showed adequate complement blockade. Our data provide essential insight for optimization of eculizumab dosing schemes and lessening of therapy burden for the patients and cost of the treatment.

Pharmacology, Pharmacokinetics and Pharmacodynamics of Eculizumab, and Possibilities for an Individualized Approach to Eculizumab

“…Since eculizumab–C5 complexes are not recycled via FcRn, C5 levels influence the target-mediated drug disposition of eculizumab. C5 levels are approximately 80–110 µg/ml in healthy controls, but are highly variable per individual and per time point depending on the underlying disease and the amount of complement activation [ 10 ].…”

“…Second, the burden for patients is considerable since eculizumab has to be administrated intravenously every 2 weeks, potentially for a lifetime. Third, there are large interindividual variations in pharmacokinetics (PK) [ 9 , 10 ], and, lastly, treatment is not without risks. The most prominent risk is the susceptibility to infection with Neisseria meningitidis (meningococcus) [ 11 ].…”

Pharmacokinetics and Pharmacodynamics Estimation of Eculizumab in a 2-Year-Old Girl With Atypical Hemolytic Uremic Syndrome: A Case Report With 4-Year Follow-Up

“…The target trough concentrations of ECZ for patients with aHUS were considered to be 50-100 µg/mL (9, 10). Volokhina et al reported that ≥50 µg/mL is an adequate ECZ concentration for maintenance treatment of patients with aHUS (10). The authors demonstrated ECZ concentrations in 11 patients with aHUS and suggested the possibility of individualized treatment.…”

Optimal duration of treatment with eculizumab in atypical hemolytic uremic syndrome (aHUS)—a question to be addressed in a scientific way

“…Further, titration of serum complexes between eculizumab and C5 levels revealed an excess of the drug up to 4 weeks after infusion in the authors' opinion, but without providing real drug quantification [49]. A short time ago, the same group of authors, this time measuring drug levels in 11 aHUS patients treated with eculizumab given at infusion intervals of 4-5 weeks, described that 80% had eculizumab trough levels > 50 μg ml and C′ fully blocked (as measured by CH50 < 10%) [50].…”