With the introduction of the complement C5-inhibitor eculizumab, a new era was entered for patients with atypical hemolytic uremic syndrome (aHUS). Eculizumab therapy very effectively reversed thrombotic microangiopathy and reduced mortality and morbidity. Initial guidelines suggested lifelong treatment and recommended prophylactic use of eculizumab in aHUS patients receiving a kidney transplant. However, there is little evidence to support lifelong therapy or prophylactic treatment in kidney transplant recipients. Worldwide, there is an ongoing debate regarding the optimal dose and duration of treatment, particularly in view of the high costs and potential side effects of eculizumab. An increasing but still limited number of case reports and small cohort studies suggest that a restrictive treatment regimen is feasible. We review the current literature and focus on the safety and efficacy of restrictive use of eculizumab. Our current treatment protocol is based on restrictive use of eculizumab. Prospective monitoring will provide more definite proof of the feasibility of such restrictive treatment.Electronic supplementary materialThe online version of this article (10.1007/s00467-018-4091-3) contains supplementary material, which is available to authorized users.

No abstract

A restrictive eculizumab regimen in aHUS appears safe and effective. Prospective studies should further evaluate the most optimal treatment strategy.

Background Eculizumab is a lifesaving yet expensive drug for atypical hemolytic uremic syndrome. Current guidelines advise a fixed-dosing schedule, which can be suboptimal and inflexible in the individual patient. Methods We evaluated pharmacokinetics (PK) and pharmacodynamics (PD) (classical pathway (CP) activity levels) of eculizumab in 48 patients, consisting of 849 time-concentration data and 569 CP activity levels. PK-PD modeling was performed with non-linear mixed effects modeling. The final model was used to develop improved dosing strategies. Results A PK-model with parallel linear and non-linear elimination rates best described the data with the parameter estimates: clearance 0.163L/day, Volume of distribution 6.42L, maximal rate 29.6mg/day, concentration for 50% of maximum rate 37.9mg/L. The PK-PD relation between eculizumab concentration and CP activity was described using an inhibitory Emax model with the parameter estimates: baseline 101%, maximal inhibitory effect 95.9%, concentration for 50% inhibition 22.0mg/L, Hill coefficient 5.42. A weight-based loading dose, followed by pharmacokinetically-guided dosing was found to improve treatment. On day 7, we predict 99.95% of the patients to reach the efficacy target (CP activity <10%), compared to 94.75% with standard dosing. Comparable efficacy was predicted during the maintenance phase, while the dosing interval could be prolonged in ∼33% of the population by means of individualized dosing. With a fixed-dose four-week dosing interval to allow holidays, treatment costs will increase with 7.1% and we predict 91% of the patients to reach the efficacy target. Conclusions A patient-friendly individualized dosing strategy of eculizumab has the potential to improve treatment response at reduced costs.